Aims: To assess the bioavailability of fluconazole (FLCZ) from phosphate pro-drug (fosfluconazole), to investigate the effect of loading doses on the time to achieve FLCZ steady state plasma concentrations and on safety, and to investigate the pharmacokinetics of fosfluconazole following once daily multiple bolus injection of fosfluconazole in healthy male volunteers.
Methods: The first study was a randomized, double-blind, double dummy, two-period crossover study. Subject received either 1000 mg fosfluconazole or 800 mg FLCZ once daily for 14 days in random order. The second study was an open label, randomized parallel group study. Subjects received one of three fosfluconazole once daily treatments: 500 mg for 10 days (no loading dose), a loading dose of 1000 mg on day 1 followed by 500 mg for 9 days (one loading dose), or loading doses of 1000 mg on days 1 and 2 followed by 500 mg for 8 days (two loading doses).
Results: The estimated mean (90% CI) bioavailability of FLCZ from fosfluconazole was 96.8% (94.5, 99.2), with a C(max,ss) ratio of 98.3% (93.3, 103.5) in the first study. Less than 1% of the administered dose of fosfluconazole was excreted unchanged in the urine and the majority (85.6%) was eliminated in the urine as FLCZ. In the second study two loading doses regimen led to earlier achievement of target steady state plasma concentrations (by day 3) compared with use of one or no loading dose (towards the end of the dosing period). Similar adverse event profiles were seen in all three treatment groups. Fosfluconazole did not accumulate after multiple dosing.
Conclusions: Multiple administration of 1000 mg fosfluconazole and 800 mg FLCZ produced equivalent systemic exposure to FLCZ. Steady state FLCZ plasma concentrations were achieved earliest when two loading doses were used.