Genetic and clinical predictors of voriconazole pharmacokinetics and hepatotoxicity: focused on CYP2C19 normal and intermediate metabolizers

BACKGROUND: Voriconazole is recommended as first-line therapy for invasive fungal infections but exhibits substantial pharmacokinetic (PK) variability and hepatotoxicity. Although CYP2C19 polymorphisms partially explain this variability, evidence regarding additional genetic determinants remains inconsistent. Studies integrating genetic and clinical factors for voriconazole PK and hepatotoxicity are limited. OBJECTIVES: To assess the association between 10 genetic variants and voriconazole trough concentrations in CYP2C19 normal (NM) and intermediate (IM) metabolizers and to identify predictors of PK variability and hepatotoxicity. METHODS: This observational study included 114 adult Chinese patients receiving voriconazole between July 2022 and May 2023. Associations between genetic variants and voriconazole trough concentrations were assessed within CYP2C19 NMs and IMs. Generalized linear models (GLMs) identified predictors of PK variability, and binary logistic regression assessed hepatotoxicity risk. RESULTS: Voriconazole trough concentrations varied over 40-fold (0.2-9 μg/mL). Nominal associations were observed for CYP3A4 (rs4646437) and NR1I2 (rs7643645, rs3814055) in NMs and for SLCO1B3 (rs4149117), SLCO2B1 (rs3781727) and NR1I2 (rs3814055) in IMs, but none remained significant after Bonferroni correction. GLM analysis identified SLCO1B3 (rs4149117), NR1I2 (rs3814055), albumin, C-reactive protein (CRP) and daily dose as predictors of PK variability. Hepatotoxicity occurred in 27.2% of patients and was associated with higher trough concentrations, whereas the NR1I2 (rs7643645) GG genotype and higher baseline platelet count were associated with reduced risk. CONCLUSIONS: Marked interindividual variability in voriconazole exposure persists among CYP2C19 NMs and IMs. Integrating therapeutic drug monitoring (TDM) with genetic and clinical factors may optimize dosing and reduce hepatotoxicity risk. Larger multicentre studies are still needed.