The pharmacokinetics and pharmacogenomics of voriconazole in pediatric Saudi patients: advancing toward precision medicine

Abstract

Voriconazole is a broad-spectrum triazole antifungal. It is used to prevent and treat invasive fungal infections in immunocompromised pediatric patients. Its clinical use is limited due to its nonlinear pharmacokinetics, high variability, and a narrow therapeutic index. Data on pharmacogenomic effects in pediatric patients are limited, particularly in the Saudi population. This study aimed to evaluate voriconazole pharmacokinetics in pediatric patients and to assess the impact of CYP2C19 genotypes on drug concentrations and clearance. A prospective observational study was conducted from October 2022 to October 2024 at two tertiary care centers in Riyadh, Saudi Arabia. Saudi pediatric patients aged between 1 and 14 years receiving voriconazole were enrolled after informed consent from guardians. Trough blood samples were collected on the fifth day of therapy and CYP2C19 genotyping (*2, *3, *17) was performed. The metabolizer status was assigned according to the Clinical Pharmacogenetics Implementation Consortium guidelines. Forty patients were included. The mean age was 67.7 ± 44.1 months, and the mean weight was 17.8 ± 9.5 kg CYP2C19 phenotypes were distributed as follows: normal metabolizers (65%), rapid metabolizers (17.5%), intermediate metabolizers (10%), and ultrarapid metabolizers (7.5%). No poor metabolizers were observed. The mean voriconazole trough concentration was 2.26 ± 2.68 mg/L and the majority (52.5%) of patients had subtherapeutic levels, 35% were within range, and 12.5% were supratherapeutic. In the multivariable analysis, only weight was significantly associated with clearance ( R 2 = 0.14, P-value = 0.02), whereas genotype showed no significant effect (P-value = 0.48). Voriconazole trough concentrations showed considerable variability among pediatric patients. Thirty-five percent of patients achieved therapeutic trough concentrations at the first trough assessment and no statistically significant association between CYP2C19 polymorphisms and voriconazole trough concentrations was observed in this cohort. However, the small sample size may have limited the detection of genetic influences. These findings support the conclusion that individualized dosing is needed to optimize therapy.