Akademik Veri Yönetim Sistemi
DRUG METABOLISM AND DISPOSITION, cilt.53, sa.10, 2025 (SCI-Expanded, Scopus)
Voriconazole, a broad-spectrum antifungal, exhibits significant interpatient variability in efficacy and safety. This study assessed the influence of genetic and nongenetic factors on its steady-state pharmacokinetics and adverse effects. In vitro studies characterized voriconazole metabolism. An ancillary analysis was conducted on data from a completed trial involving 61 healthy participants who received a loading dose of 400 mg twice daily on first day, followed by 200 mg twice daily for 8 days. On the third day of voriconazole treatment, plasma and urine samples were collected over a 12-hour period after dose administration. Multiple trough concentrations, adverse events, and laboratory values were recorded throughout the study. Voriconazole and its metabolites were quantified using liquid chromatography-tandem mass spectrometry methods. Genotyping for CYP2C9, CYP2C19, CYP3A4, and CYP3A5 variants was performed using TaqMan assays. In vitro, CYP2C19 predominantly catalyzed the formation of voriconazole N-oxide and methyl hydroxy voriconazole, whereas CYP3A4/5 catalyzed fluoropyrimidine ring hydroxylation. Steady-state voriconazole area under the concentration-time curve (AUC(0-tau)) was significantly associated with CYP2C19 genotypes (P < .01); over 9-fold reduction in AUC(0-tau) was noted in CYP2C19 *17/*17 genotype compared with CYP2C19 *2/*2 carriers. We identified voriconazole N-glucuronide in plasma for the first time. Noncompliant subjects exhibited lower voriconazole exposure (P = .0002). Visual and neurologic/psychiatric adverse effects occurred in 79.7% and 72.9% of subjects, respectively, predominantly during the loading dose phase, but showed no association with CYP2C19 genotypes. No liver abnormalities were observed. CYP2C19 polymorphisms and medication adherence significantly influence voriconazole pharmacokinetics but not safety outcomes. These findings support the consideration of CYP2C19 genotyping and adherence monitoring to optimize voriconazole therapy. SIGNIFICANCE STATEMENT: This study elucidated genetic and nongenetic factors contributing to interindividual variability in voriconazole pharmacokinetics and adverse effects. In vitro analyses identified CYP2C19 as the primary enzyme mediating voriconazole metabolism, with CYP3A4/5 playing a secondary role. In vivo, CYP2C19 polymorphisms and noncompliance significantly influenced voriconazole exposure. Mild visual and neurological/psychiatric symptoms were common during the loading phase. These findings support incorporating CYP2C19 genotyping and adherence monitoring into voriconazole dosing strategies to optimize therapeutic outcomes. (c) 2025 American Society for Pharmacology and Experimental Therapeutics. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.