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

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ClinicalTrials.gov Identifier: NCT00300677
Recruitment Status : Completed
First Posted : March 9, 2006
Results First Posted : October 14, 2009
Last Update Posted : October 14, 2009
Sponsor:
Collaborator:
McLean Hospital. Belmont, MA.
Information provided by:
Pfizer

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Basic Science
Condition Infections, Fungal
Intervention Drug: voriconazole
Enrollment 12
Recruitment Details Healthy male volunteers were recruited by 1 hospital center in the U.S. between March 2007 and August 2008.
Pre-assignment Details  
Arm/Group Title Voriconazole
Hide 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
Arm/Group Title Voriconazole
Hide 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 Number of Baseline Participants 12
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 12 participants
18-25 years 3
26-35 years 6
36-45 years 3
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 12 participants
Female
0
   0.0%
Male
12
 100.0%
1.Primary Outcome
Title Plasma Concentrations of Voriconazole
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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 Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: ng/mL
predose (Cmin) 839.50  (874.22)
2 hours postdose (C2h) 2182.33  (1190.63)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter predose: ratio adjusted geometric means
Estimated Value 300.28
Confidence Interval 90%
192.91 to 467.43
Estimation Comments Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter postdose: ratio adjusted geometric means
Estimated Value 192.72
Confidence Interval 90%
123.81 to 300.00
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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 Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: ng/mL
predose (Cmin) 2090.44  (1227.88)
2 hours postdose (C2h) 4165.20  (1806.93)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter predose: ratio adjusted geometric means
Estimated Value 300.28
Confidence Interval 90%
192.91 to 467.43
Estimation Comments Estimated value = ratio (%) of the adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole.
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter postdose: ratio adjusted geometric means
Estimated Value 192.72
Confidence Interval 90%
123.81 to 300.00
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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 Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: ng/mL
predose (Cmin) 3076.67  (841.96)
2 hours postdose (C2h) 3665.00  (958.73)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter predose: ratio adjusted geometric means
Estimated Value 12.39
Confidence Interval 90%
7.09 to 21.65
Estimation Comments Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole N-oxide.
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter postdose: ratio adjusted geometric means
Estimated Value 31.57
Confidence Interval 90%
18.06 to 55.18
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
Hide 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
Show Outcome Measure DataHide Outcome Measure Data
Hide 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
Hide 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 Number of Participants Analyzed 12
Mean (Standard Deviation)
Unit of Measure: ng/mL
predose (Cmin) 663.97  (677.55)
2 hours postdose (C2h) 1535.40  (1280.09)
Show Statistical Analysis 1 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter predose: ratio adjusted mean
Estimated Value 12.39
Confidence Interval 90%
7.09 to 21.65
Estimation Comments Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plama (reference) concentrations of voriconazole N-oxide.
Show Statistical Analysis 2 Hide 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 [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments Mixed-effects analysis of variance model with time, compartment, and time by compartment interaction as fixed effects and subjects as random effects.
Method of Estimation Estimation Parameter postdose: ratio adjusted mean
Estimated Value 31.57
Confidence Interval 90%
18.06 to 55.18
Estimation Comments Estimated value = ratio (%) of adjusted geometric means comparing brain (test) vs. plasma (reference) concentrations of voriconazole N-oxide.
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Voriconazole
Hide 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 (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Voriconazole
Affected / at Risk (%)
Total   0/12 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Voriconazole
Affected / at Risk (%)
Total   11/12 (91.67%) 
Ear and labyrinth disorders   
Ear discomfort  1  1/12 (8.33%) 
Eye disorders   
Dry eye  1  1/12 (8.33%) 
Photophobia  1  5/12 (41.67%) 
Vision blurred  1  3/12 (25.00%) 
Gastrointestinal disorders   
Abdominal pain  1  1/12 (8.33%) 
Dry mouth  1  2/12 (16.67%) 
Nausea  1  1/12 (8.33%) 
General disorders   
Fatigue  1  1/12 (8.33%) 
Pain  1  1/12 (8.33%) 
Infections and infestations   
Pharyngitis streptococcal  1  1/12 (8.33%) 
Injury, poisoning and procedural complications   
Procedural dizziness  1  2/12 (16.67%) 
Musculoskeletal and connective tissue disorders   
Musculoskeletal stiffness  1  1/12 (8.33%) 
Nervous system disorders   
Dizziness  1  2/12 (16.67%) 
Head discomfort  1  2/12 (16.67%) 
Headache  1  4/12 (33.33%) 
Paraesthesia  1  1/12 (8.33%) 
Respiratory, thoracic and mediastinal disorders   
Oropharyngeal pain  1  1/12 (8.33%) 
Skin and subcutaneous tissue disorders   
Cold sweat  1  1/12 (8.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS 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.
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.
Results Point of Contact
Name/Title: Pfizer ClinicalTrials.gov Call Center
Organization: Pfizer, Inc.
Phone: 1-800-718-1021
Responsible Party: Director, Clinical Trial Disclosure Group, Pfizer Inc
ClinicalTrials.gov Identifier: NCT00300677     History of Changes
Other Study ID Numbers: A1501079
First Submitted: March 7, 2006
First Posted: March 9, 2006
Results First Submitted: August 26, 2009
Results First Posted: October 14, 2009
Last Update Posted: October 14, 2009