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

摘要

Aims 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. Methods Twelve healthy participants received 100?mg voriconazole intravenous over 4?h, 400?mg over 6?h, 4?h, and 2?h in a crossover design. Oral midazolam (3?μg) was given at the end of infusion. Blood and urine samples were collected up to 48?h. 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. Results Area under the concentration–time curve for 400?mg intravenous voriconazole was 16% (90% confidence interval: 12–20%) lower when administered over 6?h compared to 2?h infusion. Dose‐corrected area under the concentration–time curve for 100?mg over 4?h was 34% lower compared to 400?mg over 4?h. Midazolam eCLmet was 516?ml?min –1 (420–640) following 100?mg?4?h –1 voriconazole, 152?ml?min –1 (139–166) for 400?mg?6?h –1 , 192?ml?min –1 (167–220) for 400?mg?4?h ?1 , and 202?ml?min –1 (189–217) for 400?mg?2?h –1 . Concentration giving 50% CYP inhibition of voriconazole N‐oxide was 146?±?23?μmol?l –1 for CYP3A4, and 40.2?±?4.2?μmol?l –1 for CYP2C19. Conclusions 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 2?h.