Voriconazole, a novel wide‐spectrum triazole: oral pharmacokinetics and safety

Aims  Voriconazole is a potent new triazole with broad‐spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. Methods  Sixty‐four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg −1 twice daily, 4 mg kg −1 once daily, 2 mg kg −1 three times daily, or 3 mg kg −1 twice daily. Eleven subjects received 1.5 mg kg −1 three times daily, and 21 subjects were administered placebo. Results  Voriconazole exhibited nonlinear (dose‐ and time‐dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing k el values on multiple dosing, with a consequent increase in the terminal phase t 1/2 . There was also notable intersubject variability in C max and AUC τ . The absorption of voriconazole was rapid (mean t max =  0.9–1.7 h) after single and multiple dosing and the decline in plasma concentration–time curves after t max was generally biphasic. By day 12, the C max , AUC τ , t max , and t 1/2 values for the 3 mg kg −1 twice‐daily group were 2356 ng ml −1 , 11 170 ng·h  ml −1 , 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single‐dose data. Accumulation ratios for C max and AUC τ , which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg −1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of C min values together with statistical analyses of C max and AUC τ values suggest that steady‐state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens ( C min  > 0.8 µg ml −1 ). Voriconazole was well tolerated: most treatment‐related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. Conclusions  The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg −1 twice daily.