Autoinhibitory properties of the parent but not of the N-oxide metabolite contribute to infusion rate-dependent voriconazole pharmacokinetics.

Abstract

The pharmacokinetics of voriconazole show a nonlinear dose-exposure relationship caused by inhibition of its own CYP3A-dependent metabolism. Because the magnitude of autoinhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated. Twelve healthy participants received 100mg voriconazole intravenous over 4h, 400mg over 6h, 4h, and 2h in a crossover design. Oral midazolam (3μg) was given at the end of infusion. Blood and urine samples were collected up to 48h. Voriconazole and its N-oxide metabolite were quantified using high-performance liquid chromatography coupled to tandem mass spectrometry. Midazolam estimated metabolic clearance (eCLmet) was calculated using a limited sampling strategy. Voriconazole-N-oxide inhibition of cytochrome P450 (CYP) isoforms 2C19 and 3A4 were assessed with the P450-Glo luminescence assay. Area under the concentration-time curve for 400mg intravenous voriconazole was 16% (90% confidence interval: 12-20%) lower when administered over 6h compared to 2h infusion. Dose-corrected area under the concentration-time curve for 100mg over 4h was 34% lower compared to 400mg over 4h. Midazolam eCLmet was 516mlmin-1 (420-640) following 100mg4h-1 voriconazole, 152mlmin-1 (139-166) for 400mg6h-1 , 192mlmin-1 (167-220) for 400mg4h-1 , and 202mlmin-1 (189-217) for 400mg2h-1 . Concentration giving 50% CYP inhibition of voriconazole N-oxide was 146±23μmoll-1 for CYP3A4, and 40.2±4.2μmoll-1 for CYP2C19. Voriconazole pharmacokinetics is modulated by infusion rate, an autoinhibitory contribution voriconazole metabolism by CYP3A and 2C19 and to a lesser extent its main N-oxide metabolite for CYP2C19. To avoid reduced exposure, the infusion rate should be 2h.