Effect of food on the pharmacokinetics of multiple-dose oral voriconazole

Aims Voriconazole is a new triazole antifungal agent with activity against a range of clinically important and emerging pathogens. This study determined the effect of food on the pharmacokinetics of voriconazole in healthy volunteers. Methods This was an open, randomized, two-way crossover, multiple-dose study in male volunteers. Twelve subjects received voriconazole 200 mg twice daily for 6.5 days. Each dose was administered either with food or in the fasted state, i.e. not within 2 h of food. Treatment periods were separated by a minimum 7-day washout period. Plasma samples were taken for the estimation of voriconazole plasma concentrations on days 1 and 7. Safety and toleration were assessed by monitoring of both laboratory safety tests and adverse events. Results Administering voriconazole with food significantly decreased both day 7 AUC(tau) and C-max by approximately 35% (9598-7520 ng.h ml(-1); P = 0.003) and 22% (2038-1332 ng ml(-1); P = 0.008), respectively. Administering voriconazole with food statistically significantly delayed absorption, evident from t(max) values; the mean difference for t(max) on day 7 was 1.1 h. The terminal phase rate constant was unchanged by administering voriconazole with food. The fasted terminal phase half life was 7.3 h compared with 6.6 h for the fed state. Visual inspection of C-min values suggests that steady state was achieved after 5 days in both dietary states. Voriconazole accumulation, as assessed by ratios of C-max and AUC(tau) on days 1 and 7, was statistically significantly greater when administered with food (C-max P=0.010, AUC(tau) P = 0.006). Mean C-max accumulation in the fasted state was 2.1-fold compared with 3.5-fold in the fed state. AUC(tau) accumulation in the fasted state was 3.1-fold compared with 4.2-fold in the fed state. There were no discontinuations due to adverse events or laboratory abnormalities. Treatment-related mild-to-moderate visual disturbances were experienced by six out of 12 subjects. Conclusions The bioavailability of twice-daily 200 mg voriconazole is reduced by approximately 22% as measured by AUC(tau) after multiple dosing when taken with food, compared with fasting.