Oral Bioavailability of Posaconazole in Fasted Healthy Subjects

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Abstract
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 800mg following administration of three different dose regimens to fasting adults. This was a randomised, open-label, three-way crossover study. Subjects fasted 12 hours before and 48 hours after the administration of posaconazole oral suspension (800mg) given as a single dose (regimen A), 400mg every 12 hours (regimen B) or 200mg 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. A total of 18 healthy men were enrolled in and completed the study. 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 μg · h/L, with average plasma concentrations of 162, 320 and 517 μg/L for regimens and C, respectively. These data suggest that divided daily dose administration (every 12 or 6 hours) significantly increases posaconazole exposure under fasted conditions.

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