Oral bioavailability of posaconazole in fasted healthy subjects: comparison between three regimens and basis for clinical dosage recommendations.
OBJECTIVE
Posaconazole is a potent, extended-spectrum triazole antifungal agent currently in clinical development for the treatment of invasive fungal infections. This study was conducted to compare the bioavailability and resulting serum concentrations of posaconazole 800 mg following administration of three different dose regimens to fasting adults.


METHODS
This was a randomised, open-label, three-way crossover study.


METHODS
Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800 mg) given as a single dose (regimen A), 400 mg every 12 hours (regimen B) or 200 mg every 6 hours (regimen C). Plasma posaconazole concentrations were determined for 48 hours after the initial dose and subjects completed a 1-week washout period between treatment regimens. A one-compartment oral model with first-order rate of absorption and first-order rate of elimination was fitted to the plasma concentration-time data. Differences in exposure were investigated by allowing the bioavailability fraction to vary among regimens.


METHODS
A total of 18 healthy men were enrolled in and completed the study.


RESULTS
Posaconazole relative bioavailability was estimated to be significantly different among regimens (p < 0.0001) and increased with the number of doses, such that regimen B/regimen A = 1.98 +/- 0.35, representing a 98% increase, and regimen C/regimen A = 3.20 +/- 0.69, or a 220% increase. With use of the one-compartment model, the population steady-state values for area under the concentration-time curve over 24 hours were predicted to be 3900, 7700 and 12 400 microg.h/L, with average plasma concentrations of 162, 320 and 517 microg/L for regimens A, B and C, respectively.


CONCLUSIONS
These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.
Ezzet
Farkad
F
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Wexler
David
D
Courtney
Rachel
R
Krishna
Gopal
G
Lim
Josephine
J
Laughlin
Mark
M
D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D004334:Drug Administration Schedule; D005215:Fasting / Q000378:metabolism*; D006801:Humans; D008297:Male; D008954:Models, Biological; D014230:Triazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*
D014230:Triazoles; C101425:posaconazole