Unravelling Voriconazole's Hepatic Metabolism: A Narrative Review on Factors Impacting Voriconazole-N-Oxide Exposure

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.

A comprehensive search was conducted in PubMed and Embase for articles published from 2003 to 2025 focusing on factors impacting NOX or the MR.

Twenty-one articles were included, predominantly involving adult patients from an Asian or white ethnicity. Studies were mainly set up as pharmacokinetic (PK) studies, in which associations between NOX or MR were assessed in uni- or multivariate analyses. Key covariates identified were as follows: (1) voriconazole dose (6/11 studies)-higher doses increasing NOX, although this relationship was complicated by saturated metabolism; (2) C-reactive protein (CRP) (8/9)-higher inflammation levels correlated with reduced metabolic capacity due to CYP450 enzyme downregulation; (3) age (7/12)-children exhibited higher MR, probably driven by higher clearance due to increased CYP2C19 and FMO3 expression, while older adults (> 60 years) showed decreased MR due to a decline in CYP2C19 activity; (4) CYP2C19 genotype (10/13)-poor metabolizers had lower MR and lower NOX, supporting the utility of genotyping, if available with acceptable turnaround time. A CRP threshold of 100 mg/L has been found in some studies and may serve as a crucial indicator for clinicians in optimising dosage adjustments. Although hepatic impairment is recognised as a significant covariate for voriconazole, its influence on NOX or the MR was found limited in this review. This is likely due to the exclusion of patients with hepatic impairment from most studies, which resulted in lower interindividual variation in liver function test results. While renal function does not affect voriconazole exposure, it may impact NOX or MR, as some studies suggest a higher renal clearance of NOX compared to voriconazole. However, only one of the included studies suggested that impaired renal function resulted in a higher MR, indicating NOX accumulation. Further research is however needed.

VRC dose, CRP, age and CYP2C19 genotype are the primary covariates affecting NOX or MR, and renal and liver function should also be considered in future population pharmacokinetic models and TDM protocols.