A Phase I, Open-Label, Study to Evaluate the Pharmacokinetics, Safety and Tolerability of Aclidinium Bromide in Healthy Chinese Participants
Study Details
Study Description
Brief Summary
A Phase I, single centre, open-label study to investigate the pharmacokinetics (PK), safety and tolerability of single and multiple twice daily doses of inhaled Aclidinium Bromide in healthy Chinese male and female subjects.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Screening will be performed within 21 days of dosing on Day 1. Eligible participants will be admitted to the trial center on Day -1.
Subjects will receive single dose on Day 1, twice daily regimen is from D5 to D8, and only morning dose will be given on Day 9.
During treatment period, from Day 1 through Day 11 at Visit 2, safety measurements (blood pressure, 12-lead ECG; and AE/SAE monitoring) and blood samples for PK assessments will be collected at predetermined time points.
Clinical laboratory tests (haematology, serum biochemistry and urinalysis) will be performed under fasting conditions at Day -1 at Visit 2.
A follow-up visit will be performed on Day 15.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Aclidinium Bromide 400 μg One inhalation from the 400 μg Aclidinium Bromide inhaler. |
Drug: Aclidinium Bromide 400 μg
Aclidinium Bromide 400 μg BID inhalation powder. One oral inhalation via Genuair® dry powder inhaler (DPI)
|
Outcome Measures
Primary Outcome Measures
- Cmax of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
To evaluate the maximum concentration, taken directly from the individual concentration-time curve after single dose.
- Tmax of Aclidinium Bromide and its metabolites after single dose administration [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Time to reach maximum concentration, taken directly from the individual concentration-time curves (single dose).
- λz of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Terminal rate constant, estimated by log-linear least squares (LS) regression of the terminal part of the concentration-time curve (single dose).
- t½λz of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Terminal half-life, estimated as (ln2)/λz (single dose).
- AUC(last) of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Area under the plasma concentration-curve from time zero to the time of last quantifiable concentration (single dose).
- AUC(0-∞) of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Area under the concentration-time curve from time zero extrapolated to infinity. AUC(0-∞) is estimated by AUC(last) + Clast/λz where Clast is the last observed quantifiable concentration.
- Cmin of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval (Single dose).
- CL/F of Aclidinium Bromide after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Apparent clearance for parent drug estimated as dose divided by AUC(0-∞).
- Vz/F of Aclidinium Bromide after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz.
- Css,max of Aclidinium Bromide and its metabolites after multiple dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Observed maximum concentration, taken directly from the individual concentration-time curve at steady state
- Tss,max of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Time to reach maximum concentration, taken directly from the individual concentration-time curve at steady state.
- λz of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Terminal rate constant, estimated by log-linear LS regression of the terminal part of the concentration-time curve at steady state.
- t½λz of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Terminal elimination half-life, estimated as (ln2)/λz at steady state.
- AUC(ss,tau) of Aclidinium Bromide and its metabolites (where applicable) after 5 days of repeated dose administration [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Area under the plasma concentration-curve from time zero to 12 hours post-dose at steady state.
- CL/F of Aclidinium Bromide after 5 days of repeated dose administration [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Apparent clearance for drug estimated as dose divided by AUC(ss,tau) at steady state.
- Vz/F of Aclidinium Bromide after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Apparent volume of distribution for parent drug at terminal phase (extravascular administration), estimated by dividing the apparent clearance (CL/F) by λz.
- Css,av of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Average plasma concentration during a dosing interval, estimated as AUC(ss,tau)/12.
- %Fluctuation of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Fluctuation index during a dosing interval estimated as 100*(Cmax- Cmin)/Cav (%).
- Css,min of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Observed minimum concentration, taken directly from the individual concentration-time curve within a dosing interval on Day 9
- Rac(Cmax) of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Accumulation ratio for Cmax estimated as ratio of Css,max on Day 9/Cmax on Day 1
- Rac[AUC(tau)] of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Accumulation ratio for AUC(tau) estimated as ratio of AUC(ss,tau) on Day 9/AUC(tau) on Day 1
- Rac(Cmin) of Aclidinium Bromide and its metabolites after 5 days of repeated dose administration. [Day 9 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Accumulation ratio for Cmin estimated as ratio of Css,min on Day 9/Cmin on Day 1.
- AUC(tau) of Aclidinium Bromide and its metabolites after single dose administration. [Day 1 at predose, 5 , 15 and 30 minutes, and 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36 and 48 hours post the AM dose.]
Area under the plasma concentration-curve from time zero to 12 hours after single dose.
Secondary Outcome Measures
- Adverse events (AEs)/serious AEs (SAEs) [Screening (Day -21 to Day -2) to follow-up visit (Day 15 )]
Assessment of the safety in terms of the incidences of AEs/SAEs after single and multiple dose administration of Aclidinium Bromide 400 μg
- Blood pressure [Screening (Day -21 to Day -2) to follow-up visit (Day 15)]
Assessment of the safety in terms of the blood pressure after single and multiple dose administration of Aclidinium Bromide 400 μg
- Clinical laboratory parameters (haematology) [Screening (Day -21 to Day -2) to follow-up visit (Day 15)]
Assessment of the safety in terms of haematology parameters after single and multiple dose administration of Aclidinium Bromide 400 μg
- Clinical laboratory parameters (urinalysis) [Screening (Day -21 to Day -2) to follow-up visit (Day 15)]
Assessment of the safety in terms of urinalysis parameters after single and multiple dose administration of Aclidinium Bromide 400 μg
- Clinical laboratory parameters (serum biochemistry) [Screening (Day -21 to Day -2) to follow-up visit (Day 15)]
Assessment of the safety in terms of serum biochemistry parameters after single and multiple dose administration of Aclidinium Bromide 400μg
- 12-lead ECG parameters [Screening (Day -21 to Day -2) to follow-up visit (Day 15)]
Assessment of the safety in terms of the 12-lead ECG parameters after single and multiple dose administration of Aclidinium Bromide 400μg
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Ability to communicate with medical team and staff, willing to participate in the trial, willing to give written informed consent, and comply with the trial restrictions.
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Healthy subjects: Chinese men or non-pregnant, non-lactating women, 18 through 45 years old at Visit 1 (Screening).
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Have a body mass index (BMI) ≥19 kg/m2 and ≤ 26 kg/m2
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Resting heart rate ≥ 50 beats per minute (bpm) and ≤ 100 bpm at Visit 1 (Screening) and at admission to the unit on Day -1 at Visit 2.
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Non-smoker (never smoked or has not smoked within 2 years prior to the first dose of investigational product [IP]).
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Demonstrate satisfactory technique in the use of the DPI at screening.
Exclusion Criteria:
-
History of any significant drug allergy or hypersensitivity to aclidinium bromide or other muscarinic antagonists.
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Have abnormal and clinically significant results on the physical examination, medical history, serum biochemistry, haematology, or urinalysis at Visit 1 (Screening).
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Sustained resting systolic blood pressure ≥ 140 or ≤ 90 mmHg and resting diastolic blood pressure ≥ 90 or ≤ 50 mmHg at Visit 1 (Screening) or Day -1 at Visit 2.
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Electrocardiogram (ECG) showing corrected QT interval (QTc) using Fridericia's correction (QTcF) ≥ 450 msec for male participants and ≥460 msec for female participants as indicated in the centralised reading report assessed at Screening (Visit 1).
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Have a history of alcohol or substance abuse within the previous 5 years, as reported by the participants.
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Positive results for drugs of abuse at Visit 1 (Screening).
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Positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibody and/or human immunodeficiency virus (HIV) antibodies at Visit 1 (Screening).
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Use of any medication within 2 weeks or within the equivalent time of 5 half-lives of taking the last dose (whichever is longer) before the first dose of IP, or hormonal drug products and traditional Chinese medicines within 30 days before the first dose of IP.
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Have consumed caffeine or any grapefruit-containing products within 48 hours or alcohol within 72 hours before Day -1.
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Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma draws within 60 days of Day 1 at Visit 2.
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Have participated in a blood/plasma donation or blood loss greater than 400 mL within 90 days, or greater than 200 mL within 30 days prior to screening (Visit 1).
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Recent history of a disease or condition that would result in any residual upper respiratory airways/lung inflammatory process or residual limited lung function at the time of Day 1 at Visit 2.
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History of confirmed COVID-19 infection.
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Have any gastrointestinal, hepatic, or renal condition that might affect the absorption, distribution, biotransformation, or excretion of aclidinium bromide.
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Inability to be venipunctured or tolerate venous access as determined by the PI or designee.
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Participants unable to give their consent, or participants of consenting age but under guardianship, or vulnerable participants.
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In the opinion of the PI, participants who are unlikely to comply with the protocol requirements, instructions, and trial-related restrictions.
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Participant is a relative of the Investigator or any sub-investigator, research assistant, pharmacist, trial coordinator, or other staff or directly involved in the conduct of the clinical trial.
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Any other conditions that, in the Investigator's opinion, might have indicated the participant to be unsuitable for the study (e.g. confirmed/suspected COVID-19)
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Research Site | Chengdu | China | 610000 |
Sponsors and Collaborators
- AstraZeneca
Investigators
- Principal Investigator: Weimin Li, West China Hostial, Sichuan University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- D6572C00002
- M-AS273-01