Genetic and clinical predictors of voriconazole pharmacokinetics and hepatotoxicity: focused on CYP2C19 normal and intermediate metabolizers - PubMed
4 hours ago
- #hepatotoxicity
- #voriconazole
- #pharmacokinetics
- Voriconazole is a first-line therapy for invasive fungal infections but has significant pharmacokinetic (PK) variability and hepatotoxicity risks.
- CYP2C19 polymorphisms partially explain PK variability, but additional genetic determinants are inconsistent.
- The study assessed 10 genetic variants and their association with voriconazole trough concentrations in CYP2C19 normal (NM) and intermediate metabolizers (IM).
- 114 adult Chinese patients were included in the observational study from July 2022 to May 2023.
- Voriconazole trough concentrations varied widely (0.2-9 μg/mL), showing over 40-fold interindividual variability.
- Nominal associations were found for CYP3A4 (rs4646437) and NR1I2 (rs7643645, rs3814055) in NMs, and SLCO1B3 (rs4149117), SLCO2B1 (rs3781727), and NR1I2 (rs3814055) in IMs, but none survived Bonferroni correction.
- GLM analysis identified SLCO1B3 (rs4149117), NR1I2 (rs3814055), albumin, CRP, and daily dose as predictors of PK variability.
- Hepatotoxicity occurred in 27.2% of patients and was linked to higher trough concentrations.
- NR1I2 (rs7643645) GG genotype and higher baseline platelet count were associated with reduced hepatotoxicity risk.
- The study suggests integrating TDM with genetic and clinical factors to optimize dosing and reduce hepatotoxicity risk.
- Larger multicentre studies are needed for further validation.