Unravelling Voriconazole's Hepatic Metabolism: A Narrative Review on Factors Impacting Voriconazole-N-Oxide Exposure
Abstract
Background: Voriconazole (VRC), a triazole antifungal agent, is recommended as primary treatment for invasive aspergillosis. Due to its unpredictable dose-exposure relationship, therapeutic drug monitoring (TDM) is recommended. Despite TDM, the probability of achieving therapeutic targets is only approximately 50%. This highlights the need for new dosing strategies. Calculating the metabolic ratio (MR) of NOX, the principal N-oxide metabolite of voriconazole primarily formed by the genetically polymorphic CYP2C19 enzyme, to VRC concentrations could serve as a surrogate for phenotype information. This is particularly relevant since the CYP2C19 genotype is often unavailable in acute clinical settings. Moreover, genotype may be less informative during inflammation due to a phenomenon known as 'phenoconversion', where inflammation masks genotype effects through downregulation of CYP450 enzymes. However, before integrating NOX in population PK models and/or as an adjunct in voriconazole TDM flowcharts, it is important to understand the factors impacting NOX exposure, and hence the MR. The objective of this narrative review is therefore to summarise recent literature on patient- and drug-related covariates impacting NOX exposure.
Methods: A comprehensive search was conducted in PubMed and Embase for articles published from 2003 to 2025 focusing on factors impacting NOX or the MR.
Results/discussion: Twenty-one articles were included, predominantly involving adult patients from an…
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