Infections, Fungal
Conditions
Keywords
Pharmacokinetics, Voriconazole, Magnetic Resonance Spectroscopy
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.
Interventions
DRUGvoriconazole
Multiple oral doses of voriconazole at 400 mg loading twice daily followed by 200 mg maintenance twice daily
Sponsors
McLean Hospital. Belmont, MA.
Pfizer
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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). |
| 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. |
| 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). |
Countries
United States
Participant flow
Recruitment details
Healthy male volunteers were recruited by 1 hospital center in the U.S. between March 2007 and August 2008.
Participants by arm
| Arm | Count |
|---|---|
| Voriconazole 400 mg every 12 hours on Day 1; 200 mg every 12 hours on Day 2; 200 mg on Day 3 | 12 |
| Total | 12 |
Baseline characteristics
| Characteristic | Voriconazole |
|---|---|
| Age, Customized 18-25 years | 3 participants |
| Age, Customized 26-35 years | 6 participants |
| Age, Customized 36-45 years | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 11 / 12 |
| serious Total, serious adverse events | 0 / 12 |
Outcome results
Primary
Brain Concentrations of N-oxide Metabolite
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | Brain Concentrations of N-oxide Metabolite | predose (Cmin) | 663.97 ng/mL | Standard Deviation 677.55 |
| Voriconazole | Brain Concentrations of N-oxide Metabolite | 2 hours postdose (C2h) | 1535.40 ng/mL | Standard Deviation 1280.09 |
Comparison: 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.90% CI: [7.09, 21.65]ANOVA
Comparison: 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.90% CI: [18.06, 55.18]ANOVA
Primary
Brain Concentrations of Voriconazole
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | Brain Concentrations of Voriconazole | predose (Cmin) | 2090.44 ng/mL | Standard Deviation 1227.88 |
| Voriconazole | Brain Concentrations of Voriconazole | 2 hours postdose (C2h) | 4165.20 ng/mL | Standard Deviation 1806.93 |
Comparison: 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.90% CI: [192.91, 467.43]ANOVA
Comparison: 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.90% CI: [123.81, 300]ANOVA
Primary
Plasma Concentrations of N-oxide Metabolite
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | Plasma Concentrations of N-oxide Metabolite | predose (Cmin) | 3076.67 ng/mL | Standard Deviation 841.96 |
| Voriconazole | Plasma Concentrations of N-oxide Metabolite | 2 hours postdose (C2h) | 3665.00 ng/mL | Standard Deviation 958.73 |
Comparison: 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.90% CI: [7.09, 21.65]ANOVA
Comparison: 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.90% CI: [18.06, 55.18]ANOVA
Primary
Plasma Concentrations of Voriconazole
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
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Voriconazole | Plasma Concentrations of Voriconazole | predose (Cmin) | 839.50 ng/mL | Standard Deviation 874.22 |
| Voriconazole | Plasma Concentrations of Voriconazole | 2 hours postdose (C2h) | 2182.33 ng/mL | Standard Deviation 1190.63 |
Comparison: 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.90% CI: [192.91, 467.43]ANOVA
Comparison: 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.90% CI: [123.81, 300]ANOVA