Dose-Dependent Bioavailability and CYP3A Inhibition Contribute to Non-Linear Pharmacokinetics of Voriconazole

Abstract

Voriconazole is both a substrate and a potent inhibitor of cytochrome P450 (CYP) 3A. It has a high bioavailability and non-linear pharmacokinetics. We investigated the pharmacokinetics and metabolism of 50 mg and 400 mg doses of intravenous and oral voriconazole in 14 healthy volunteers. Concurrently, we determined systemic and presystemic CYP3A activity with microdosed midazolam. Bioavailability of voriconazole 50 mg was 39 % compared with 86 % of the 400 mg dose. Voriconazole area under the concentration-time curve extrapolated to infinity (AUC) was 416 and 16,700 h·ng/mL for the 50 and 400 mg oral doses, respectively, and 1110 and 19,760 h·ng/mL for the 50 and 400 mg intravenous doses, respectively. Midazolam metabolism was dose-dependently inhibited by voriconazole. Dose-dependent autoinhibition of CYP3A-dependent first-pass metabolism and systemic metabolism is a possible explanation for the dose-dependent bioavailability and elimination of voriconazole, either as additional mechanism to, or instead of, saturation of presystemic metabolism. Higher bioavailability and non-linear pharmacokinetics are expected to be a common property of drugs that are substrates and inhibitors of CYP3A, e.g. clarithromycin.

Influence of Experimental Cryptococcal Meningitis in Wistar Rats on Voriconazole Brain Penetration Assessed by Microdialysis

“…This phenomenon for basic drugs such as VRC (pK a ϭ 12.71) (2) produces the drug's ionization and may result in an ion-trapping effect. Given that VRC presents major elimination (98%) by the metabolic pathway, including isoen- zymes CYP2C19, CYP3A4, and CYP2C9, liver injury could reduce its metabolism, reducing the value of V M in infected animals (33)(34)(35).…”

Drug‐drug interactions between triazole antifungal agents used to treat invasive aspergillosis and immunosuppressants metabolized by cytochrome P450 3A4

“…Voriconazole exhibits non‐linear pharmacokinetics such that exposure increases disproportionately with increasing dosages . That may be due in part to saturable metabolism, although more recent evidence suggests that it may instead (or in addition) be related to dose‐dependent autoinhibition of CYP3A4 activity . In any event, considerable inter‐ and intra‐subject variability in plasma concentrations of voriconazole has been observed and is at least partly due to allelic variants of the CYP2C19 gene that confer reduced or enhanced enzyme activity in subjects characterized as poor or extensive/ultra‐rapid metabolizers, respectively .…”

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

“…Therefore, switching the route of administration is possible without dose adaptation . Voriconazole's pharmacokinetics are nonlinear with dose‐dependent bioavailability and dose‐dependent elimination half‐life . The bioavailability of smaller doses is considerably lower, e.g.…”