To Determine The Amount Of Voriconazole In The Brain After 2 Loading Doses And 3 Maintenance Doses Over 3 Days

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00300677
• Collaborator: McLean Hospital. Belmont, MA. (Other)
• Enrollment: 12
• Location: 1
• Arm: 1
• Duration (Months): 17.1
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

To determine the amount of voriconazole in the brain after 2 loading doses and 3 maintenance doses over 3 days and compare it to the amount of voriconazole in the plasma.

Condition or Disease	Intervention/Treatment	Phase
Infections, Fungal	Drug: voriconazole	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Assessment Of Voriconazole Penetration Into The Brain By Fluorine-Magnetic Resonance Spectroscopy
• Study Start Date: Mar 1, 2007
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: voriconazole voriconazole twice daily	Drug: voriconazole; Multiple oral doses of voriconazole at 400 mg loading twice daily followed by 200 mg maintenance twice daily; Other Names: Vfend

Outcome Measures

Primary Outcome Measures

1. Plasma Concentrations of Voriconazole [Day 3: pre-dose, 2 hours post-dose]

   Mean plasma voriconazole concentrations (nanograms per milliliter [ng/mL]) pre-dose (Cmin) and two hours post-dose (C2h). Plasma samples were assayed using a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.

2. Brain Concentrations of Voriconazole [Day 3: pre-dose, 2 hours post-dose]

   Mean brain concentrations (ng/mL) of voriconazole pre-dose and 2 hours post-dose measured by Fluorine (F) Magnetic Resonance Spectroscopy (F-MRS).

3. Plasma Concentrations of N-oxide Metabolite [Day 3: pre-dose, 2 hours post-dose]

   Mean plasma concentrations of voriconazole N-oxide metabolite (ng/mL) pre-dose and 2 hours post-dose. Plasma samples were assayed using a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.

4. Brain Concentrations of N-oxide Metabolite [Day 3: pre-dose, 2 hours post-dose]

   Mean brain concentrations (ng/mL) of voriconazole N-oxide metabolite pre-dose and 2 hours post-dose measured by Fluorine (F) Magnetic Resonance Spectroscopy (F-MRS).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subjects must be willing and able to provide informed consent.

• Subjects must be willing and able to be confined at the Clinical Research Unit as required by the protocol.

Exclusion Criteria:

• Subjects with any condition affecting drug absorption.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Belmont	Massachusetts	United States	02478-1041

Sponsors and Collaborators

• Pfizer
• McLean Hospital. Belmont, MA.

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00300677
• Other Study ID Numbers: A1501079
• First Posted: Mar 9, 2006
• Last Update Posted: Oct 14, 2009
• Last Verified: Oct 1, 2009

• Keywords provided by , ,: Pharmacokinetics; Voriconazole; Magnetic Resonance Spectroscopy
• Additional relevant MeSH terms: Mycoses; Voriconazole

Study Results

Participant Flow

Recruitment Details	Healthy male volunteers were recruited by 1 hospital center in the U.S. between March 2007 and August 2008.

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Period Title: Overall Study
STARTED	12
COMPLETED	12
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Overall Participants	12
Age, Customized (participants) [Number]
18-25 years	3 25%
26-35 years	6 50%
36-45 years	3 25%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	12 100%

Outcome Measures

1. Primary Outcome

Title	Plasma Concentrations of Voriconazole
Description	Mean plasma voriconazole concentrations (nanograms per milliliter [ng/mL]) pre-dose (Cmin) and two hours post-dose (C2h). Plasma samples were assayed using a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.
Time Frame	Day 3: pre-dose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: subjects included in the statistical analysis of pharmacokinetic parameters had the pharmacokinetic parameter of interest. N=number of observations (non-missing concentrations).

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Measure Participants	12
predose (Cmin)	839.50 (874.22)
2 hours postdose (C2h)	2182.33 (1190.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 pre-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	predose: ratio adjusted geometric means
	Estimated Value	300.28
	Confidence Interval	() 90%; 192.91 to 467.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 post-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	postdose: ratio adjusted geometric means
	Estimated Value	192.72
	Confidence Interval	() 90%; 123.81 to 300.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.

2. Primary Outcome

Title	Brain Concentrations of Voriconazole
Description	Mean brain concentrations (ng/mL) of voriconazole pre-dose and 2 hours post-dose measured by Fluorine (F) Magnetic Resonance Spectroscopy (F-MRS).
Time Frame	Day 3: pre-dose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: subjects included in the statistical analysis of pharmacokinetic parameters had the pharmacokinetic parameter of interest. N=number of observations (non-missing concentrations).

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Measure Participants	12
predose (Cmin)	2090.44 (1227.88)
2 hours postdose (C2h)	4165.20 (1806.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 pre-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	predose: ratio adjusted geometric means
	Estimated Value	300.28
	Confidence Interval	() 90%; 192.91 to 467.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of the adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 post-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	postdose: ratio adjusted geometric means
	Estimated Value	192.72
	Confidence Interval	() 90%; 123.81 to 300.00
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.

3. Primary Outcome

Title	Plasma Concentrations of N-oxide Metabolite
Description	Mean plasma concentrations of voriconazole N-oxide metabolite (ng/mL) pre-dose and 2 hours post-dose. Plasma samples were assayed using a validated, sensitive, and specific high performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) method.
Time Frame	Day 3: pre-dose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: subjects included in the statistical analysis of pharmacokinetic parameters had the pharmacokinetic parameter of interest. N=number of observations (non-missing concentrations).

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Measure Participants	12
predose (Cmin)	3076.67 (841.96)
2 hours postdose (C2h)	3665.00 (958.73)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 pre-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole N-oxide. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	predose: ratio adjusted geometric means
	Estimated Value	12.39
	Confidence Interval	() 90%; 7.09 to 21.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole N-oxide.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 post-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole N-oxide. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	postdose: ratio adjusted geometric means
	Estimated Value	31.57
	Confidence Interval	() 90%; 18.06 to 55.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole N-oxide.

4. Primary Outcome

Title	Brain Concentrations of N-oxide Metabolite
Description	Mean brain concentrations (ng/mL) of voriconazole N-oxide metabolite pre-dose and 2 hours post-dose measured by Fluorine (F) Magnetic Resonance Spectroscopy (F-MRS).
Time Frame	Day 3: pre-dose, 2 hours post-dose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Analysis Set: subjects included in the statistical analysis of pharmacokinetic parameters had the pharmacokinetic parameter of interest. N=number of observations (non-missing concentrations).

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
Measure Participants	12
predose (Cmin)	663.97 (677.55)
2 hours postdose (C2h)	1535.40 (1280.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 pre-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole N-oxide. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	predose: ratio adjusted mean
	Estimated Value	12.39
	Confidence Interval	() 90%; 7.09 to 21.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plama (reference) concentrations of voriconazole N-oxide.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Voriconazole
	Comments	Other estimated parameter represents the Day 3 post-dose ratio of the adjusted geometric means comparing brain vs. plasma concentrations of voriconazole N-oxide. Natural-log transformed concentrations of voriconazole were analyzed using a mixed-effects model to obtain the adjusted mean difference (Test-Reference) and 90% confidence interval for the difference which were exponentiated to provide estimates of the ratio of the adjusted geometric means and 90% CI for the ratio.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	postdose: ratio adjusted mean
	Estimated Value	31.57
	Confidence Interval	() 90%; 18.06 to 55.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole N-oxide.

Adverse Events

Arm/Group Title	Voriconazole
Arm/Group Description	400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3
All Cause Mortality
	Voriconazole
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Voriconazole
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	Voriconazole
	Affected / at Risk (%)	# Events
Total	11/12 (91.7%)
Ear and labyrinth disorders
Ear discomfort	1/12 (8.3%)
Eye disorders
Dry eye	1/12 (8.3%)
Photophobia	5/12 (41.7%)
Vision blurred	3/12 (25%)
Gastrointestinal disorders
Abdominal pain	1/12 (8.3%)
Dry mouth	2/12 (16.7%)
Nausea	1/12 (8.3%)
General disorders
Fatigue	1/12 (8.3%)
Pain	1/12 (8.3%)
Infections and infestations
Pharyngitis streptococcal	1/12 (8.3%)
Injury, poisoning and procedural complications
Procedural dizziness	2/12 (16.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal stiffness	1/12 (8.3%)
Nervous system disorders
Dizziness	2/12 (16.7%)
Head discomfort	2/12 (16.7%)
Headache	4/12 (33.3%)
Paraesthesia	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/12 (8.3%)
Skin and subcutaneous tissue disorders
Cold sweat	1/12 (8.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of < 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), < 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.