Understanding Voriconazole Metabolism: A Middle-Out Physiologically-Based Pharmacokinetic Modelling Framework Integrating In Vitro and Clinical Insights.

ABSTRACT:

Background and objective

Voriconazole (VRC), a broad-spectrum antifungal drug, exhibits nonlinear pharmacokinetics (PK) due to saturable metabolic processes, autoinhibition and metabolite-mediated inhibition on their own formation. VRC PK is also characterised by high inter- and intraindividual variability, primarily associated with cytochrome P450 (CYP) 2C19 genetic polymorphism. Additionally, recent in vitro findings indicate that VRC main metabolites, voriconazole N-oxide (NO) and hydroxyvoriconazole (OHVRC), inhibit CYP enzymes responsible for VRC metabolism, adding to its PK variability. This variability poses a significant risk of therapeutic failure or adverse events, which are major challenges in VRC therapy. Understanding the underlying processes and sources of these varia

SUBMITTER: Saleh A 

PROVIDER: S-EPMC11573852 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature