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

<jats:p><jats:bold>Aims </jats:bold> 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.</jats:p><jats:p><jats:bold>Methods </jats:bold> 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<jats:sup>−1</jats:sup> twice daily, 4 mg kg<jats:sup>−1</jats:sup> once daily, 2 mg kg<jats:sup>−1</jats:sup> three times daily, or 3 mg kg<jats:sup>−1</jats:sup> twice daily. Eleven subjects received 1.5 mg kg<jats:sup>−1</jats:sup> three times daily, and 21 subjects were administered placebo.</jats:p><jats:p><jats:bold>Results </jats:bold> Voriconazole exhibited nonlinear (dose‐ and time‐dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing <jats:italic>k</jats:italic><jats:sub>el</jats:sub> values on multiple dosing, with a consequent increase in the terminal phase <jats:italic>t</jats:italic><jats:sub>1/2</jats:sub>. There was also notable intersubject variability in <jats:italic>C</jats:italic><jats:sub>max</jats:sub> and AUC<jats:sub>τ</jats:sub>. The absorption of voriconazole was rapid (mean <jats:italic>t</jats:italic><jats:sub>max</jats:sub>=  0.9–1.7 h) after single and multiple dosing and the decline in plasma concentration–time curves after <jats:italic>t</jats:italic><jats:sub>max</jats:sub> was generally biphasic. By day 12, the <jats:italic>C</jats:italic><jats:sub>max</jats:sub>, AUC<jats:sub>τ</jats:sub>, <jats:italic>t</jats:italic><jats:sub>max</jats:sub>, and <jats:italic>t</jats:italic><jats:sub>1/2</jats:sub> values for the 3 mg kg<jats:sup>−1</jats:sup> twice‐daily group were 2356 ng ml<jats:sup>−1</jats:sup>, 11 170 ng·h  ml<jats:sup>−1</jats:sup>, 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 <jats:italic>C</jats:italic><jats:sub>max</jats:sub> and AUC<jats:sub>τ</jats:sub>, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg<jats:sup>−1</jats:sup> 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 <jats:italic>C</jats:italic><jats:sub>min</jats:sub> values together with statistical analyses of <jats:italic>C</jats:italic><jats:sub>max</jats:sub> and AUC<jats:sub>τ</jats:sub> 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 <jats:italic>Aspergillus</jats:italic> spp., <jats:italic>Candida</jats:italic> spp., and for most emerging fungal pathogens (<jats:italic>C</jats:italic><jats:sub>min</jats:sub> > 0.8 µg ml<jats:sup>−1</jats:sup>). Voriconazole was well tolerated: most treatment‐related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing.</jats:p><jats:p><jats:bold>Conclusions </jats:bold> 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<jats:sup>−1</jats:sup> twice daily.</jats:p>