Phase 1 Three Part SAD, MAD & Cross-Over Study of ZP-059 in Healthy and Asthmatic Subjects
Study Details
Study Description
Brief Summary
The primary safety objectives were:
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Part 1: To determine the safety and tolerability of single doses of ZP-059 in healthy subjects
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Part 2: To determine the safety and tolerability of multiple doses of ZP-059 in subjects with mild stable asthma
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Part 3: To determine the safety and tolerability of single doses of ZP-059 in subjects with mild to moderate stable asthma.
The primary PK objectives were:
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Part 1: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 in healthy subjects
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Part 2: To characterize systemic PK of voriconazole and N-oxide voriconazole after multiple doses of ZP-059 in subjects with mild stable asthma
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Part 3: To characterize systemic PK of voriconazole and N-oxide voriconazole after single doses of ZP-059 and single doses of oral voriconazole in subjects with mild to moderate stable asthma.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
This was an integrated Phase 1, single centre, multi-part, open-label study in both healthy subjects (Part 1), subjects with mild stable asthma (Part 2) and subjects with mild to moderate stable asthma (Part 3). In all three parts of the study every effort was made to include as close as possible an equal balance between male and female subjects.
This study assessed safety, tolerability and PK of single and multiple ascending doses of ZP-059 capsules administered as dry powder for inhalation in Part 1 to healthy volunteers (single ascending dose; SAD) and in Part 2 to subjects with mild asthma (multiple ascending dose; MAD), respectively.
In Part 3, the bioavailability of ZP-059 in subjects with mild to moderate stable asthma were compared to that of oral voriconazole. Part 3 started only after review of safety data from cohorts 1 to 4 of Part 1 (SAD) have been completed. Parts 2 and 3 of the study also explored voriconazole concentrations in induced sputum samples in asthmatic subjects.
As part of the safety and tolerability assessment, this study investigated the effects of ZP-059 on airway function in both mild and mild to moderate stable asthma subjects.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: Part 1 - ZP-059 5mg Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 1 - ZP-059 10mg Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 1 - ZP-059 20mg Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 1 - ZP-059 40mg Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 2 - ZP-059 10mg bid Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 2 - ZP-059 20mg bid Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 2 - ZP-059 40mg qd Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) administered via DPI (RS01 monodose device) on Days 1 to 10. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
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Experimental: Part 3 - ZP-059 / Oral Voriconazole Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
Drug: oral voriconazole
Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study.
Other Names:
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Experimental: Part 3 - Oral Voriconazole / ZP-059 Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. |
Drug: Voriconazole inhaled
Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1.
Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10.
Part 3 (2-period crossover): eligible subjects received a 4 [20mg BID] inhaled doses of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study.
ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler).
Other Names:
Drug: oral voriconazole
Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study.
Other Names:
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Outcome Measures
Primary Outcome Measures
- Number of Participants With Treatment-Emergent Adverse Events (TEAE) [Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug).]
An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of IMP, whether or not considered related to the study IMP.
Secondary Outcome Measures
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-12 for Part 1) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
- Cmax for Voriconazole and N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
- Kel for Voriconazole and N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
- CL/F for Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
- Vz/F for Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
Vz/F=Apparent volume of distribution during terminal phase.
- MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
- MR Cmax for N-oxide Voriconazole - Part 1 [Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose).]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-24 for Part 2) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
- Cmax for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
- Kel for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
- CL/F for Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
- Swing for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Swing for voriconazole and N-oxide voriconazole = [(Cmax - Cmin) / Cmin]*100%
- AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Area under the serum concentration time curve for the dosing interval
- Css,av for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Css,av or Css(ave): Average drug concentration at steady state; Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly
- Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration.
- Rac for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Accumulation ratio. The drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation.
- Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 [Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity.
- MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
- MR Cmax N-oxide Voriconazole - Part 2 [Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours)]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
- Cmax for Voriconazole and N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given;
- Vz/F for Voriconazole - Part 3 [Only at Day 10]
Vz/F=Apparent volume of distribution during terminal phase.
- AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-96 for Part 3) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity
- Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2 (Pre-dose, 0.25h, 0.75h 1.5h, 2h ,3h ,4h ,6h ,8h ,12h ,16h , 24h ,48h after dosing)]
Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value.
- CL/F for Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies.
- Kel for Voriconazole and N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h.
- Vz/F for Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
Vz/F=Apparent volume of distribution during terminal phase.
- MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t)
- MR Cmax for N-oxide Voriconazole - Part 3 [Day 1 of the respective treatment period 1 or 2]
MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
- Bioavailability of Voriconazole - Cmax [On Day 1 in Parts 1-3 and on Day 10 in Part 2]
The Cmax estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The Cmax was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, Cmax was estimated only on Day1. In Part 2, Cmax was estimated on Day 10.
- Bioavailability of Voriconazole - AUC-inf [On Day 1 in Parts 1-3 and on Day 10 in Part 2]
The AUC0-inf estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The AUC0-inf was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, AUC0-inf was estimated on Day 1. In part 2, AUC0-in f was estimated on Day 10.
Eligibility Criteria
Criteria
Inclusion Criteria (part 1):
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Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
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Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
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Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
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BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
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Are willing and able to comply with all aspects of the protocol.
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FEV1 ≥80% of the predicted value and FEV1/FVC ratio > 0.70; at screening.
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Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.
Inclusion Criteria (part 2):
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Subjects with mild stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
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Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to Day 1.
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Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method
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Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s).
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Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
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Body mass index (BMI) ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
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Are willing and able to comply with all aspects of the protocol.
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Subject is being treated with short acting beta-agonists alone or in conjunction with low to medium doses of ICS.
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Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
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Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1.
Inclusion Criteria (part 3):
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Subjects with mild to moderate stable asthma with a documented physician confirmed diagnosis of asthma for at least 3 months prior to screening.
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Asthma assessed by investigator as being stable for at least 4 weeks prior to screening and prior to randomisation.
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Female subjects must be either of non-childbearing potential or if of childbearing potential use a highly effective birth control method .
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Male subjects with female partners of childbearing potential must be vasectomised with documented medical assessment of the surgical success or use highly effective contraception together with their female partner(s)
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Subject must agree not to donate semen or ova/oocytes during the study and for 14 days after the last dose of IMP.
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BMI ≥ 18.0 and ≤ 35.0 kg/m2 at Screening.
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Are willing and able to comply with all aspects of the protocol.
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Subject is being treated with low to medium doses of ICS with or without long-acting beta-agonists.
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Pre-bronchodilator FEV1 ≥70% of the predicted value at screening.
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Able to demonstrate the correct inhalation technique for use of delivery device during the study at screening and pre-dose Day 1, Treatment Period 1.
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Able to produce a sputum sample with a minimum weight of 50 mg at screening.
Exclusion Criteria (part 1):
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Subjects who are Chinese or Japanese.
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Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
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Participation in other interventional studies for the duration of the study.
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Subjects who are study site employees or immediate family members of a study site or sponsor employee.
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History of any drug or alcohol abuse in the past 2 years prior to screening.
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Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
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Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
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A confirmed positive urine cotinine test at screening or Day -1.
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Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
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Smoking history of >5 pack years at screening.
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Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
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Female subject with a positive pregnancy test at screening or pre-dose on Day 1.
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Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
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Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
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Positive urine drugs of abuse test or alcohol breath test result at screening or Day -1.
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History of or currently infected with/carrier of human immunodeficiency virus (HIV).
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Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
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Evidence or history of clinically significant cardiovascular, renal, hepatic, endocrine, immunological or autoimmune, dermatological, ophthalmological, chronic respiratory or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
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Subjects with congestive heart failure or a history of congestive heart failure.
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12-lead ECGs demonstrating a mean QTcF interval >450 msec for males or QTcF interval
470 msec for females at screening or pre-dose Day 1.
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History of severe cough or bronchospasm upon inhalation of any inhalation product.
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Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
-
Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
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Presence or history of clinically significant allergy, including drug allergies, but excluding untreated, mild seasonal allergies, as judged by the investigator. Hay fever is allowed unless it is active.
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Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
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Planned or elective surgery or hospitalisations for the duration of the study that may interfere with study logistics or safety.
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Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
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Subjects who are taking, or have taken, any prescribed or over-the-counter drug (other than ≤4 g per day of paracetamol, hormonal contraception or hormone replacement therapy), dietary supplements or CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study. Exceptions may apply on a case by case basis, if considered not to interfere with the objectives of the study, as agreed by the Principal Investigator and sponsor's medical monitor.
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Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
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Any use of voriconazole in the 3 months prior to Day 1.
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Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
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Upper respiratory tract infection (excluding otitis media), fever, acute or chronic cough within 14 days of Day 1, or lower respiratory tract infection within the last 4 weeks prior to Day 1.
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Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
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Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the investigator would make the subject inappropriate for entry into the study.
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Failure to satisfy the investigator of fitness to participate for any reason.
Exclusion Criteria (part 2 and 3):
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Subjects who are Chinese or Japanese.
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Subjects who have received any IMP in a clinical research study within the previous 3 months prior to Day 1.
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Participation in other interventional studies for the duration of the study.
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Subjects who are study site employees, or immediate family members of a study site or sponsor employee.
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Subjects who have previously received IMP in this study.
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History of any drug or alcohol abuse in the past 2 years prior to screening.
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Regular alcohol consumption in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, a 25 mL shot of 40% spirit or a 125 mL glass of wine depending on type).
-
Current tobacco or marijuana smokers and those who have smoked within the last 12 months prior to screening or prior to Day 1.
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A confirmed positive urine cotinine test at screening or Day -1.
-
Current users of e-cigarettes or nicotine replacement products and those who have used these products within the last 12 months prior to screening or prior to Day 1.
-
Smoking history of >5 pack years at screening.
-
Females of childbearing potential who are pregnant or lactating, or who plan to become pregnant during the study. A woman is considered of childbearing potential unless she is permanently sterile (hysterectomy, bilateral salpingectomy, bilateral oophorectomy, bilateral tubal occlusion/ligation) or is postmenopausal (had no menses for 12 months without an alternative medical cause).
-
Female subject with a positive pregnancy test at screening or pre-dose Day 1.
-
Subjects who do not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening.
-
Evidence or history of clinically significant abnormal biochemistry, haematology or urinalysis at screening, as judged by the investigator; the investigator should contact the medical monitor and /or the sponsor if required.
-
Positive urine drugs of abuse test result (unless in the opinion of the investigator this can be explained by the subject's current medications) at screening or Day -1; unexpected positive results may require discussion with sponsor).
-
Positive alcohol breath test at screening or Day -1.
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History of or currently infected with/carrier of HIV.
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Positive HBsAg, HCV Ab or HIV results. Subjects who are HBs antibody positive or HB core antibody positive are not excluded provided the HBsAg result is negative. Subjects who are HCV Ab positive are not excluded if a subsequent HCV RNA test is negative.
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Evidence or history of clinically significant cardiovascular, renal, hepatic, dermatologic, ophthalmologic or gastrointestinal disease, neurological or psychiatric disorder, as judged by the investigator.
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Evidence of history of endocrine, immunological, autoimmune disease that would affect the subject's safety or confound the assessment of study endpoints in the opinion of the investigator.
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Current diagnosis of any chronic airways disease other than asthma such as Chronic Obstructive Pulmonary Disease, pulmonary fibrosis, CF, Churg-Strauss syndrome, bronchiectasis.
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Evidence of ventricular dysfunction such as congestive cardiac failure (CCF) or a history of CCF assessed at screening and pre-dose Day 1.
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12-lead ECG demonstrating a mean QTcF interval >450 msec for males or >470 msec for females at screening or pre-dose Day 1.
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Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients.
-
Have had allergies to or hypersensitivity reactions after administration of voriconazole or other antifungal azoles.
-
Presence or history of clinically significant allergy, including drug allergies, as judged by the investigator. Hay fever is allowed unless it is active.
-
Major trauma or surgery within the last 3 months prior to screening or prior to Day 1.
-
Planned or elective surgery, hospitalisations for the duration of the study that may interfere with study logistics or safety.
-
Donation or loss of more than 400 mL of blood within the previous 3 months prior to screening.
-
Subjects who are taking, or have taken, any prescribed or over-the-counter drugs that are CYP3A4 or CYP2C19 inhibitors in the 14 days (or 5 half-lives, whichever is longer) prior to Day 1 and for the duration of the study.
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Subjects who are taking or have taken any herbal remedies or CYP3A4 or CYP2C19 inducers in the 28 days prior to Day 1.
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Subjects who have received a live or killed/inactive vaccine in the 14 days prior to Day 1.
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Presence of hoarseness or oropharyngeal candidiasis at screening or prior to dosing on Day 1.
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Any use of voriconazole in the 3 months prior to Day 1.
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History of life-threatening asthma, defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest and/or hypoxic seizures.
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Hospitalisation (including accident and emergency visits) for the treatment of asthma within 3 months prior to screening or prior to Day 1 or have been hospitalised or have attended the accident and emergency for asthma more than twice in the 12 months prior to screening.
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Occurrence of asthma exacerbations or respiratory tract infections within 4 weeks prior to screening or prior to Day 1.
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Recent (within the last 4 weeks prior to Day 1) clinically significant bacterial, viral or fungal infection that required systemic (oral or intravenous) antibiotics, antivirals or antifungals; topical treatments, other than antifungals, are allowed.
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Other social, psychiatric, surgical or medical conditions, or screening laboratory abnormalities that may increase subject risk associated with study participation or may interfere with the interpretation of study results and, in the judgement of the Investigator would make the subject inappropriate for entry into the study.
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Failure to satisfy the investigator of fitness to participate for any reason.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Medicines Evaluation Unit Ltd. (MEU) | Manchester | United Kingdom | M239QZ |
Sponsors and Collaborators
- Zambon SpA
Investigators
- Study Director: Sukh Dave Singh, Prof, MD,, The Medicine Evaluation Unit (MEU) Ltd, Langley building,
Study Documents (Full-Text)
More Information
Publications
None provided.- Z7240J01
- 2019-004031-23
Study Results
Participant Flow
Recruitment Details | The investigator or his/her representative explained the nature of the study to the subject and answered all questions regarding the study. Subjects had to be informed that their participation was voluntary. Subjects were required to sign a statement of informed consent that met the requirements of UK regulations, ICH E6 GCP guidelines, General Data Protection Regulation, and the IEC or study site requirements. The authorized person who obtained the informed consent had to also sign the ICF. |
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Pre-assignment Detail | Subjects were screened for eligibility to participate in the study within 28 days before dosing (Day 1). Part 2 and Part 3 subjects who had completed the initial screening visit attended the study site on Day -4 or Day -3, for Covid-19 reverse transcriptase - polymerase chain reaction (RT-PCR) test, together with additional daily tympanic temperature measurements, and other tests as applicable. Subjects were then be admitted to the study site on the evening of Day -1. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 / Oral Voriconazole | Part 3 - Oral Voriconazole / ZP-059 |
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Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Period Title: Overall Study | |||||||||
STARTED | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 8 | 8 |
COMPLETED | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 8 | 8 |
NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline Characteristics
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 / Oral Voriconazole | Part 3 - Oral Voriconazole / ZP-059 | Total |
---|---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Total of all reporting groups |
Overall Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 8 | 8 | 58 |
Age (Count of Participants) | ||||||||||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
8
100%
|
8
100%
|
58
100%
|
>=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Sex: Female, Male (Count of Participants) | ||||||||||
Female |
3
50%
|
3
50%
|
3
50%
|
2
33.3%
|
2
33.3%
|
2
33.3%
|
3
50%
|
1
12.5%
|
2
25%
|
21
36.2%
|
Male |
3
50%
|
3
50%
|
3
50%
|
4
66.7%
|
4
66.7%
|
4
66.7%
|
3
50%
|
7
87.5%
|
6
75%
|
37
63.8%
|
Race (NIH/OMB) (Count of Participants) | ||||||||||
American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
12.5%
|
1
12.5%
|
2
3.4%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Black or African American |
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
3.4%
|
White |
6
100%
|
5
83.3%
|
6
100%
|
6
100%
|
5
83.3%
|
5
83.3%
|
6
100%
|
6
75%
|
7
87.5%
|
52
89.7%
|
More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
1
1.7%
|
Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
12.5%
|
0
0%
|
1
1.7%
|
Region of Enrollment (participants) [Number] | ||||||||||
United Kingdom |
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
6
100%
|
8
100%
|
8
100%
|
58
100%
|
Outcome Measures
Title | Number of Participants With Treatment-Emergent Adverse Events (TEAE) |
---|---|
Description | An AE is any untoward medical occurrence in a patient or clinical study subject, temporally associated with the use of IMP, whether or not considered related to the study IMP. |
Time Frame | Part 1: screening (Day -28 to -1) to follow-up (8 to 12 days after last dose); part 2: screening (Day -28 to -1) to follow-up (11-17 days after last dose); Part 3: screening (Day -28 to -1) to follow-up (8-12 days after last dose of study drug). |
Outcome Measure Data
Analysis Population Description |
---|
Safety Analysis Set (SAF): subjects who received at least 1 IMP dose, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 20mg | Part 3 - Oral Voriconazole 200mg |
---|---|---|---|---|---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 6 | 6 | 6 | 6 | 6 | 6 | 6 | 16 | 16 |
Total number of subjects with at least 1 TEAE |
0
0%
|
3
50%
|
2
33.3%
|
2
33.3%
|
5
83.3%
|
4
66.7%
|
4
66.7%
|
9
112.5%
|
7
87.5%
|
Total number of subjects with at least 1 serious TEAE |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Total number of subjects with at least 1 mild TEAE |
0
0%
|
2
33.3%
|
2
33.3%
|
1
16.7%
|
3
50%
|
3
50%
|
2
33.3%
|
8
100%
|
5
62.5%
|
Total number of subjects with at least 1 moderate TEAE |
0
0%
|
1
16.7%
|
0
0%
|
1
16.7%
|
2
33.3%
|
1
16.7%
|
2
33.3%
|
1
12.5%
|
2
25%
|
Total number of subjects with at least 1 severe TEAE |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
Total number of subjects with at least 1 treatment-related TEAE |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
4
66.7%
|
0
0%
|
1
16.7%
|
7
87.5%
|
0
0%
|
Total number of subjects with at least 1 non treatment-related TEAE |
0
0%
|
3
50%
|
2
33.3%
|
2
33.3%
|
1
16.7%
|
4
66.7%
|
3
50%
|
2
25%
|
7
87.5%
|
Title | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 1 |
---|---|
Description | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-12 for Part 1) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
AUC0-t Voriconazole |
24.36
(1.45)
|
73.89
(1.16)
|
187.76
(1.35)
|
328.37
(1.19)
|
AUC0-t N-oxide Voriconazole |
298.15
(1.11)
|
573.55
(1.26)
|
804.24
(1.11)
|
1835.81
(1.09)
|
AUC0-inf Voriconazole |
40.00
(1.00)
|
78.94
(1.18)
|
203.96
(1.44)
|
377.19
(1.20)
|
AUC0-inf N-oxide Voriconazole |
337.40
(1.12)
|
652.99
(1.32)
|
865.80
(1.07)
|
1977.21
(1.11)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.62 | |
Confidence Interval |
(2-Sided) 90% 0.424 to 0.821 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0363 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.21 | |
Confidence Interval |
(2-Sided) 90% 1.050 to 1.362 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 13.48 | |
Confidence Interval |
(2-Sided) 90% 10.096 to 17.994 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.85 | |
Confidence Interval |
(2-Sided) 90% 1.728 to 1.963 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 5
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0201 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.87 | |
Confidence Interval |
(2-Sided) 90% 0.789 to 0.960 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 6
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 6.16 | |
Confidence Interval |
(2-Sided) 90% 5.253 to 7.217 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 7
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.81 | |
Confidence Interval |
(2-Sided) 90% 0.661 to 0.958 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 8
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.1278 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.12 | |
Confidence Interval |
(2-Sided) 90% 0.990 to 1.245 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 9
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 9.43 | |
Confidence Interval |
(2-Sided) 90% 6.834 to 13.012 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 10
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.98 | |
Confidence Interval |
(2-Sided) 90% 1.860 to 2.106 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 11
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0082 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.79 | |
Confidence Interval |
(2-Sided) 90% 0.670 to 0.912 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 12
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 5.86 | |
Confidence Interval |
(2-Sided) 90% 4.627 to 7.421 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Cmax for Voriconazole and N-oxide Voriconazole - Part 1 |
---|---|
Description | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
Voriconazole |
8.44
(1.27)
|
18.52
(1.39)
|
53.37
(1.32)
|
94.33
(1.18)
|
N-oxide voriconazole |
57.70
(1.12)
|
103.16
(1.32)
|
145.79
(1.30)
|
286.63
(1.15)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.2575 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.12 | |
Confidence Interval |
(2-Sided) 90% -0.060 to 0.308 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0491 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.17 | |
Confidence Interval |
(2-Sided) 90% 1.030 to 1.316 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 11.17 | |
Confidence Interval |
(2-Sided) 90% 8.435 to 14.803 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | General power constant model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.25 | |
Confidence Interval |
(2-Sided) 90% 1.135 to 1.363 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 5
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0003 |
Comments | ||
Method | General power linear model | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 0.74 | |
Confidence Interval |
(2-Sided) 90% 0.634 to 0.843 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 6
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax, 40mg vs 5mg | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean difference |
Estimated Value | 4.97 | |
Confidence Interval |
(2-Sided) 90% 3.946 to 6.254 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 1 |
---|---|
Description | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
Tmax Voriconazole |
1.57
(1.11)
|
1.50
(1.00)
|
1.50
(1.00)
|
1.50
(1.00)
|
Tmax N-oxide voriconazole |
1.57
(1.11)
|
1.50
(1.00)
|
1.85
(1.29)
|
1.65
(1.15)
|
T1/2 Voriconazole |
2.67
(1.42)
|
3.07
(1.09)
|
3.20
(1.17)
|
3.63
(1.22)
|
T1/2 N-oxide voriconazole |
3.60
(1.08)
|
3.59
(1.21)
|
3.38
(1.27)
|
4.43
(1.26)
|
Title | Kel for Voriconazole and N-oxide Voriconazole - Part 1 |
---|---|
Description | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
Voriconazole |
0.30
(1.52)
|
0.23
(1.09)
|
0.22
(1.17)
|
0.19
(1.22)
|
N-oxide voriconazole |
0.19
(1.08)
|
0.19
(1.21)
|
0.20
(1.27)
|
0.16
(1.26)
|
Title | CL/F for Voriconazole - Part 1 |
---|---|
Description | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
Geometric Mean (Standard Deviation) [L/h] |
131.2
(1.04)
|
124.6
(1.17)
|
97.7
(1.39)
|
108.7
(1.22)
|
Title | Vz/F for Voriconazole - Part 1 |
---|---|
Description | Vz/F=Apparent volume of distribution during terminal phase. |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 3 | 6 | 6 | 6 |
Geometric Mean (Standard Deviation) [liters] |
614.3
(1.09)
|
553.1
(1.14)
|
450.9
(1.25)
|
569.6
(1.20)
|
Title | MR AUC0-t, MR AUC0-inf for N-oxide Voriconazole - Part 1 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
MR AUC0-t |
12.25
(1.36)
|
7.76
(1.40)
|
4.28
(1.43)
|
5.59
(1.14)
|
MR AUC0-inf |
10.92
(1.20)
|
8.18
(1.39)
|
4.92
(1.42)
|
6.12
(1.08)
|
Title | MR Cmax for N-oxide Voriconazole - Part 1 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
Time Frame | Part 1: at day 1 (pre-dose, at 1.5h-2h-3h-4h-12h post dose). |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 | 6 |
Geometric Mean (Standard Deviation) [ratio] |
6.84
(1.27)
|
5.57
(1.73)
|
2.73
(1.51)
|
3.04
(1.31)
|
Title | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-24 for Part 2) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
AUC0-t Voriconazole - Day 1 |
69.65
(1.39)
|
139.29
(1.21)
|
329.28
(1.19)
|
AUC0-inf Voriconazole - Day 1 |
78.20
(1.40)
|
155.72
(1.16)
|
358.13
(1.20)
|
AUC0-t Voriconazole - Day 10 |
91.00
(1.36)
|
256.04
(1.41)
|
480.22
(1.27)
|
AUC0-inf Voriconazole - Day 10 |
97.78
(1.35)
|
258.66
(1.44)
|
493.04
(1.29)
|
AUC0-t N-oxide Voriconazole - Day 1 |
391.28
(1.19)
|
769.65
(1.15)
|
1990.76
(1.23)
|
AUC0-inf N-oxide Voriconazole - Day 1 |
439.14
(1.20)
|
849.27
(1.17)
|
2001.85
(1.24)
|
AUC0-t N-oxide Voriconazole - Day 10 |
728.68
(1.31)
|
1784.63
(1.40)
|
3353.43
(1.27)
|
AUC0-inf N-oxide Voriconazole - Day 10 |
752.99
(1.32)
|
1807.93
(1.47)
|
3174.66
(1.19)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0004 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.00 | |
Confidence Interval |
(2-Sided) 90% 1.528 to 2.617 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.73 | |
Confidence Interval |
(2-Sided) 90% 3.612 to 6.187 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.81 | |
Confidence Interval |
(2-Sided) 90% 2.017 to 3.925 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-t Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 5.28 | |
Confidence Interval |
(2-Sided) 90% 3.783 to 7.361 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 5
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.97 | |
Confidence Interval |
(2-Sided) 90% 1.615 to 2.396 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 6
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 5.09 | |
Confidence Interval |
(2-Sided) 90% 4.178 to 6.196 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 7
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0002 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.45 | |
Confidence Interval |
(2-Sided) 90% 1.791 to 3.349 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 8
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-t Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.60 | |
Confidence Interval |
(2-Sided) 90% 3.365 to 6.294 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 9
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0005 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.99 | |
Confidence Interval |
(2-Sided) 90% 1.524 to 2.602 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 10
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.58 | |
Confidence Interval |
(2-Sided) 90% 3.505 to 5.984 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 11
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0003 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.65 | |
Confidence Interval |
(2-Sided) 90% 1.851 to 3.781 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 12
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole AUC0-inf Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 5.04 | |
Confidence Interval |
(2-Sided) 90% 3.587 to 7.088 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 13
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 1.93 | |
Confidence Interval |
(2-Sided) 90% 1.569 to 2.384 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 14
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.56 | |
Confidence Interval |
(2-Sided) 90% 3.608 to 5.759 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 15
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0007 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.40 | |
Confidence Interval |
(2-Sided) 90% 1.694 to 3.402 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 16
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole AUC0-inf Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.22 | |
Confidence Interval |
(2-Sided) 90% 2.975 to 5.974 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Cmax for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole - Day 1 |
19.87
(1.29)
|
40.42
(1.33)
|
96.77
(1.16)
|
Voriconazole - Day 10 |
21.38
(1.21)
|
57.11
(1.33)
|
127.54
(1.20)
|
N-oxide Voriconazole - Day 1 |
71.66
(1.24)
|
144.43
(1.11)
|
339.11
(1.15)
|
N-oxide Voriconazole - Day 10 |
102.78
(1.30)
|
217.76
(1.23)
|
412.40
(1.21)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0003 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.03 | |
Confidence Interval |
(2-Sided) 90% 1.562 to 2.650 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.87 | |
Confidence Interval |
(2-Sided) 90% 3.740 to 6.345 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.67 | |
Confidence Interval |
(2-Sided) 90% 2.081 to 3.429 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for Voriconazole Cmax Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 5.97 | |
Confidence Interval |
(2-Sided) 90% 4.647 to 7.658 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 5
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.02 | |
Confidence Interval |
(2-Sided) 90% 1.688 to 2.406 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 6
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.73 | |
Confidence Interval |
(2-Sided) 90% 3.964 to 5.650 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 7
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 10mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 2.12 | |
Confidence Interval |
(2-Sided) 90% 1.655 to 2.711 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 8
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | Statistics for N-oxide Voriconazole Cmax day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Slope |
Estimated Value | 4.01 | |
Confidence Interval |
(2-Sided) 90% 3.135 to 5.135 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Tmax Voriconazole - Day 1 |
1.50
(1.00)
|
1.50
(1.00)
|
1.57
(1.11)
|
Tmax Voriconazole - Day 10 |
1.50
(1.00)
|
1.50
(1.00)
|
1.50
(1.00)
|
Tmax N-oxide Voriconazole - Day 1 |
1.65
(1.15)
|
1.50
(1.00)
|
1.65
(1.15)
|
Tmax N-oxide Voriconazole - Day 10 |
1.57
(1.11)
|
1.57
(1.11)
|
2.33
(1.45)
|
T1/2 Voriconazole - Day 1 |
3.60
(1.36)
|
3.53
(1.25)
|
3.24
(1.08)
|
T1/2 Voriconazole - Day 10 |
4.40
(1.41)
|
5.15
(1.29)
|
4.48
(1.15)
|
T1/2 N-oxide Voriconazole - Day 1 |
3.45
(1.08)
|
3.20
(1.11)
|
3.82
(1.44)
|
T1/2 N-oxide Voriconazole - Day 10 |
4.52
(1.16)
|
5.04
(1.24)
|
4.14
(1.21)
|
Title | Kel for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole - Day 1 |
0.19
(1.35)
|
0.20
(1.25)
|
0.21
(1.08)
|
Voriconazole - Day 10 |
0.16
(1.41)
|
0.13
(1.29)
|
0.15
(1.15)
|
N-oxide Voriconazole - Day 1 |
0.20
(1.08)
|
0.22
(1.11)
|
0.18
(1.44)
|
N-oxide Voriconazole - Day 10 |
0.15
(1.16)
|
0.14
(1.24)
|
0.17
(1.21)
|
Title | CL/F for Voriconazole - Part 2 |
---|---|
Description | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Geometric Mean (Standard Deviation) [L/h] |
120.9
(1.29)
|
93.1
(1.32)
|
93.5
(1.25)
|
Title | Swing for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Swing for voriconazole and N-oxide voriconazole = [(Cmax - Cmin) / Cmin]*100% |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
10.50
(1.48)
|
9.62
(1.68)
|
55.16
(1.63)
|
N-oxide Voriconazole |
4.60
(1.16)
|
3.81
(1.48)
|
20.65
(2.70)
|
Title | AUCtau for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Area under the serum concentration time curve for the dosing interval |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
82.82
(1.30)
|
215.56
(1.32)
|
427.57
(1.25)
|
N-oxide Voriconazole |
620.89
(1.28)
|
1438.74
(1.31)
|
2803.51
(1.20)
|
Title | Css,av for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Css,av or Css(ave): Average drug concentration at steady state; Steady-state concentration (Css) occurs when the amount of a drug being absorbed is the same amount that's being cleared from the body when the drug is given continuously or repeatedly |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
6.91
(1.30)
|
17.95
(1.32)
|
35.64
(1.25)
|
N-oxide Voriconazole |
51.75
(1.28)
|
119.88
(1.31)
|
233.63
(1.20)
|
Title | Fluctuation for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Peak trough fluctuation in serum concentrations within one dosing interval at steady state. Fluctuation - Over the Dosing Interval - is expressed as percentage concentration. |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
281.0
(1.15)
|
284.9
(1.24)
|
350.8
(1.10)
|
N-oxide Voriconazole |
162.8
(1.08)
|
141.8
(1.21)
|
163.8
(1.30)
|
Title | Rac for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Accumulation ratio. The drug accumulation ratio (Rac) is the ratio of accumulation of a drug under steady state conditions as compared to a single dose. The higher the value, the more the drug accumulates in the body. An Rac of 1 means no accumulation. |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
1.19
(1.17)
|
1.55
(1.29)
|
1.30
(1.27)
|
N-oxide Voriconazole |
1.59
(1.11)
|
1.87
(1.20)
|
1.41
(1.10)
|
Title | Rlinear for Voriconazole and N-oxide Voriconazole - Part 2 |
---|---|
Description | Rlinear means linearity ratio for Area Under the Serum Concentration-Time Curve from time zero to infinity. |
Time Frame | Part 2: Only at Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
Voriconazole |
1.06
(1.14)
|
1.38
(1.25)
|
1.19
(1.26)
|
N-oxide Voriconazole |
1.42
(1.12)
|
1.70
(1.21)
|
1.30
(1.17)
|
Title | MR AUC0-t, MR AUC0-inf and MR AUCtau for N-oxide Voriconazole - Part 2 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
MR AUC0-t N-oxide Voriconazole - Day 1 |
5.62
(1.50)
|
5.53
(1.32)
|
6.04
(1.27)
|
MR AUC0-inf N-oxide Voriconazole - Day 1 |
5.68
(1.52)
|
5.45
(1.29)
|
5.55
(1.20)
|
MR AUC0-t N-oxide Voriconazole - Day 10 |
8.01
(1.40)
|
6.97
(1.32)
|
6.98
(1.16)
|
MR AUC0-inf N-oxide Voriconazole - Day 10 |
7.70
(1.40)
|
6.99
(1.34)
|
7.11
(1.18)
|
MR AUCtau N-oxide Voriconazole - Day 10 |
7.50
(1.39)
|
6.68
(1.30)
|
6.56
(1.20)
|
Title | MR Cmax N-oxide Voriconazole - Part 2 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
Time Frame | Part 2: Day 1 (1.5, 2, 3, 4, and 12 hours post-0-hour dose) and Day 10 (post-0-hour dose at 1.5, 2, 3, 4, and 12 hours) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 6 | 6 |
N-oxide Voriconazole - Day 1 |
3.61
(1.50)
|
3.57
(1.40)
|
3.50
(1.22)
|
N-oxide Voriconazole - Day 10 |
4.81
(1.38)
|
3.81
(1.34)
|
3.23
(1.37)
|
Title | Cmax for Voriconazole and N-oxide Voriconazole - Part 3 |
---|---|
Description | Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given; |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
Voriconazole |
108.08
(1.42)
|
863.22
(1.44)
|
N-oxide Voriconazole |
151.43
(1.25)
|
1589.05
(1.25)
|
Title | Vz/F for Voriconazole - Part 3 |
---|---|
Description | Vz/F=Apparent volume of distribution during terminal phase. |
Time Frame | Only at Day 10 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd |
---|---|---|---|
Arm/Group Description | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). |
Measure Participants | 6 | 5 | 6 |
Geometric Mean (Standard Deviation) [Liters] |
767.1
(1.47)
|
714.3
(1.25)
|
604.9
(1.13)
|
Title | AUC0-t, AUC0-inf for Voriconazole and N-oxide Voriconazole - Part 3 |
---|---|
Description | AUC0-t = Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) (AUC0-96 for Part 3) AUC0-inf = Area under the serum concentration time curve from time 0 to infinity |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
AUC0-t Voriconazole |
290.02
(1.87)
|
3726.68
(1.91)
|
AUC0-inf Voriconazole |
269.61
(1.56)
|
3800.41
(1.92)
|
AUC0-t N-oxide Voriconazole |
1128.69
(1.27)
|
21504.52
(1.20)
|
AUC0-inf N-oxide Voriconazole |
1154.35
(1.26)
|
21788.46
(1.20)
|
Title | Tmax and T1/2 for Voriconazole and N-oxide Voriconazole - Part 3 |
---|---|
Description | Tmax= Time to maximum concentration (Cmax). T 1/2 = Elimination half-life: the time taken for the plasma concentration to fall by half its original value. |
Time Frame | Day 1 of the respective treatment period 1 or 2 (Pre-dose, 0.25h, 0.75h 1.5h, 2h ,3h ,4h ,6h ,8h ,12h ,16h , 24h ,48h after dosing) |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
Tmax Voriconazole |
0.43
(3.64)
|
1.16
(1.40)
|
Tmax N-oxide Voriconazole |
1.74
(1.31)
|
2.76
(1.52)
|
T1/2 Voriconazole |
5.13
(1.27)
|
6.93
(1.32)
|
T1/2 N-oxide Voriconazole |
4.68
(1.19)
|
6.42
(1.35)
|
Title | CL/F for Voriconazole - Part 3 |
---|---|
Description | Apparent clearance: Equal to the drug dose divided by the area-under-the-curve; is an important pharmacokinetic parameter and plays an important role in the selection of a safe and tolerable dose for first-in-human studies. |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 15 | 16 |
Geometric Mean (Standard Deviation) [L/h] |
74.2
(1.57)
|
52.4
(1.93)
|
Title | Kel for Voriconazole and N-oxide Voriconazole - Part 3 |
---|---|
Description | Kel (Elimination rate constant): is a value used to describe the rate at which a drug is removed from the human system. It is equivalent to the fraction of a substance that is removed per unit time measured at any particular instant and has units of 1/h. |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
Voriconazole |
0.14
(1.26)
|
0.10
(1.31)
|
N-oxide Voriconazole |
0.15
(1.19)
|
0.11
(1.34)
|
Title | Vz/F for Voriconazole - Part 3 |
---|---|
Description | Vz/F=Apparent volume of distribution during terminal phase. |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 15 | 16 |
Geometric Mean (Standard Deviation) [Liters] |
549.0
(1.46)
|
526.0
(1.69)
|
Title | MR AUC0-t and MR AUC0-inf for N-oxide Voriconazole - Part 3 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Area under the serum concentration time curve from time 0 to time t (hours) (AUC0-t) |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
MR AUC0-t |
3.89
(1.92)
|
5.77
(1.81)
|
MR AUC0-inf |
4.38
(1.48)
|
5.74
(1.79)
|
Title | MR Cmax for N-oxide Voriconazole - Part 3 |
---|---|
Description | MR = metabolite ratio. Metabolite ratios (as appropriate) will be calculated for AUC and Cmax parameters. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given. |
Time Frame | Day 1 of the respective treatment period 1 or 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|
Arm/Group Description | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 16 | 16 |
Geometric Mean (Standard Deviation) [ratio] |
1.40
(1.44)
|
1.84
(1.54)
|
Title | Bioavailability of Voriconazole - Cmax |
---|---|
Description | The Cmax estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The Cmax was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, Cmax was estimated only on Day1. In Part 2, Cmax was estimated on Day 10. |
Time Frame | On Day 1 in Parts 1-3 and on Day 10 in Part 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 20mg | Part 2 - ZP-059 20mg Bid | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 6 | 6 | 16 | 16 |
Parts 1, 2, and 3 - Day 1 |
53.37
(1.32)
|
40.42
(1.33)
|
108.08
(1.42)
|
863.22
(1.44)
|
Part 2 - Day 10 |
57.11
(1.33)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Part 3 - ZP-059 20mg: Oral Voriconazole (200mg VFEND) | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 0.13 | |
Confidence Interval |
(2-Sided) 90% 0.107 to 0.146 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 2.10 | |
Confidence Interval |
(2-Sided) 90% 1.545 to 2.853 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 2 Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 2.63 | |
Confidence Interval |
(2-Sided) 90% 1.953 to 3.544 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 2 Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 1.87 | |
Confidence Interval |
(2-Sided) 90% 1.386 to 2.520 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Bioavailability of Voriconazole - AUC-inf |
---|---|
Description | The AUC0-inf estimated from Part 3 was analyzed to assess the relative bioavailability of inhaled ZP-059 to oral voriconazole. The AUC0-inf was compared between asthma subjects in Part 3 and healthy subjects in Part 1 and separately with asthma subjects in Part 2 to assess the relative bioavailability of ZP-059 dose taken in Part 3 in these populations. In Part 1 and 3, AUC0-inf was estimated on Day 1. In part 2, AUC0-in f was estimated on Day 10. |
Time Frame | On Day 1 in Parts 1-3 and on Day 10 in Part 2 |
Outcome Measure Data
Analysis Population Description |
---|
PK Concentration Set: SAF subjects who had at least 1 quantifiable serum PK concentration recorded, analyzed according to the treatment actually taken. |
Arm/Group Title | Part 1 - ZP-059 20mg | Part 2 - ZP-059 20mg Bid | Part 3 - ZP-059 | Part 3 - Oral Voriconazole |
---|---|---|---|---|
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. |
Measure Participants | 6 | 6 | 16 | 16 |
Parts 1, 2, and 3 - Day 1 |
203.96
(1.44)
|
155.72
(1.16)
|
269.61
(1.56)
|
3800.41
(1.92)
|
Part 2 - Day 10 |
258.66
(1.44)
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 20mg, Part 1 - ZP-059 40mg |
---|---|---|
Comments | Part 3 ZP-059 20mg: Oral Voriconazole (200mg VFEND®) | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 0.07 | |
Confidence Interval |
(2-Sided) 90% 0.059 to 0.075 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 2
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 5mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 1.27 | |
Confidence Interval |
(2-Sided) 90% 0.850 to 1.891 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 3
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 2 Day 1 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 2.63 | |
Confidence Interval |
(2-Sided) 90% 1.953 to 3.544 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Statistical Analysis 4
Statistical Analysis Overview | Comparison Group Selection | Part 1 - ZP-059 10mg, Part 1 - ZP-059 20mg |
---|---|---|
Comments | ZP-059 20mg: Part 3 / Part 2 Day 10 | |
Type of Statistical Test | Other | |
Comments | ||
Statistical Test of Hypothesis | p-Value | |
Comments | ||
Method | ||
Comments | ||
Method of Estimation | Estimation Parameter | Geometric mean ratio |
Estimated Value | 1.87 | |
Confidence Interval |
(2-Sided) 90% 1.386 to 2.520 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Adverse Events
Time Frame | Throughout Part 1 (Day 1, Day 2, Day 3 by phone, Day 5 on return visit) until Days 9-13 by follow-up phone calls. Throughout Part 2 from Day 1 to Day 11, on Day 14 and Day 17 on return visits until Days 11-17 after the last dose by follow-up phone calls. Throughout Part 3 from Day 1 until Day 4 | |||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Adverse Event Reporting Description | ||||||||||||||||||
Arm/Group Title | Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 | Part 3 - Oral Voriconazole | |||||||||
Arm/Group Description | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 1: 5mg (1 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 2: 10mg (2 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 3: 20mg (4 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 1: administration of single ascending doses (SAD) of ZP-059. Cohort 4: 40mg (8 x 5 mg capsule) ZP-059 single dose administered via DPI (RS01 monodose device) on Day 1. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Days 1 to 10. Cohort 1: 10mg (2 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 2: 20mg (4 x 5 mg capsule) ZP-059 twice daily (bid) administered via DPI (RS01 monodose device) for 9 days and once in the morning of Day 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Part 2: administration of multiple ascending doses (MAD) of ZP-059 on Day 1 to 10. Cohort 3: 40mg (8 x 5 mg capsule) ZP-059 once daily (qd) d) administered via DPI (RS01 monodose device) on Days 1 to 10. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). | Crossover treatment period: Single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI, and a single dose of oral voriconazole (200 mg Vfend® tablet) on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | Crossover treatment period: Single dose of oral voriconazole (200 mg Vfend® tablet), and a single inhaled dose (20 mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 of the respective treatment period with a washout period of at least 96 hours. Voriconazole inhaled: Part 1 (SAD): eligible subjects received a single ascending inhaled dose (5 mg, 10 mg, 20 mg, and 40 mg) of ZP-059 5mg capsules administered via dry powder inhaler (DPI) on the morning of Day 1. Part 2 (MAD): eligible subjects received 2 (10mg twice daily [BID]) or 4 [20mg BID]) inhaled doses of ZP-059 5mg capsules administered via DPI BID for 9 days and once in the morning of Day 10, or 8 inhaled doses of ZP-059 5 mg capsules (40mg once daily [QD]) for 10 days. For QD dosing, subjects received QD doses of ZP-059 (at hour 0) on Days 1 to 10. Part 3 (2-period crossover): eligible subjects received a single inhaled dose (20mg) of ZP-059 5mg capsules administered via DPI on the morning of Day 1 according to the crossover scheme of the study. ZP-059 (inhaled voriconazole) was provided in clear, colorless size 3 hydroxypropylmethylcellulose hard capsules, which were individually and manually triggered by a breath actuated inhalation device (RS01 monodose inhaler). oral voriconazole: Part 3 (2-period crossover): eligible subjects received a single dose of oral voriconazole (200mg oral film-coated tablet, Vfend) on the morning of Day 1 according to the crossover scheme of the study. | |||||||||
All Cause Mortality |
||||||||||||||||||
Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 | Part 3 - Oral Voriconazole | ||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/16 (0%) | 0/16 (0%) | |||||||||
Serious Adverse Events |
||||||||||||||||||
Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 | Part 3 - Oral Voriconazole | ||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/6 (0%) | 0/16 (0%) | 0/16 (0%) | |||||||||
Other (Not Including Serious) Adverse Events |
||||||||||||||||||
Part 1 - ZP-059 5mg | Part 1 - ZP-059 10mg | Part 1 - ZP-059 20mg | Part 1 - ZP-059 40mg | Part 2 - ZP-059 10mg Bid | Part 2 - ZP-059 20mg Bid | Part 2 - ZP-059 40mg qd | Part 3 - ZP-059 | Part 3 - Oral Voriconazole | ||||||||||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 0/6 (0%) | 3/6 (50%) | 2/6 (33.3%) | 2/6 (33.3%) | 5/6 (83.3%) | 4/6 (66.7%) | 4/6 (66.7%) | 9/16 (56.3%) | 7/16 (43.8%) | |||||||||
Ear and labyrinth disorders | ||||||||||||||||||
Ear discomfort | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Gastrointestinal disorders | ||||||||||||||||||
Abdominal distension | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Abdominal pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Diarrhea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Flatulence | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
General disorders | ||||||||||||||||||
Chest discomfort | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 2 | 7/16 (43.8%) | 7 | 1/16 (6.3%) | 1 |
Catheter site bruise | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Catheter site pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Vessel puncture site pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Immune system disorders | ||||||||||||||||||
Seasonal allergy | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Infections and infestations | ||||||||||||||||||
Nasopharyngitis | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Injury, poisoning and procedural complications | ||||||||||||||||||
Stress fracture | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Investigations | ||||||||||||||||||
FEV decreased | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||||||||||||||||
Musculoskeletal stiffness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Nervous system disorders | ||||||||||||||||||
Headache | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 2/6 (33.3%) | 2 | 1/6 (16.7%) | 1 | 1/6 (16.7%) | 1 | 2/6 (33.3%) | 2 | 4/16 (25%) | 4 | 3/16 (18.8%) | 3 |
Migraine | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Dysgeusia | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 3/6 (50%) | 3 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Dizziness | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Dizziness postural | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Tension headache | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 1/16 (6.3%) | 1 |
Reproductive system and breast disorders | ||||||||||||||||||
Dysmenorrhoea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||
Oropharyngeal pain | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/16 (6.3%) | 1 | 1/16 (6.3%) | 1 |
Wheezing | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Cough | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Rhinorrhea | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Throat irritation | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Skin and subcutaneous tissue disorders | ||||||||||||||||||
Dermatitis atopic | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Erythema | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Vascular disorders | ||||||||||||||||||
Hot Flush | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 1/6 (16.7%) | 1 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/16 (0%) | 0 | 0/16 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title | Arnd Mueller, MD |
---|---|
Organization | Zambon SpA |
Phone | +39 02 665241 |
clinicaltrials@zambongroup.com |
- Z7240J01
- 2019-004031-23