Pharmacogenomic Profiling of Voriconazole Enables Predicting Its Toxicity in Pediatric Leukemia and Hematopoietic Stem Cell Transplant Recipients—A Prospective Study From North India

Voriconazole has variable pharmacokinetics, significant interactions, and a narrow therapeutic window, requiring drug monitoring. This study evaluated CYP2C19 genotype and voriconazole levels in North Indian children, a population with limited pharmacogenomic data. It is a prospective single-center study (August 2023-January 2025) in children with leukemia/HSCT. Voriconazole levels were measured using the ARK assay; CYP2C19 genotyping was done by PCR-Sanger, with phenotypes assigned per CPIC guidelines. A total of 102 patients (mean age 6.56 ± 4.22 years; M:F 1.9:1) were enrolled, with B-ALL being most common diagnosis (77.5%). Voriconazole levels showed marked variability, with only 52.9% in the therapeutic range (1-5.5 µg/mL). Intermediate (33.3%) and normal (30.4%) metabolizers predominated. CYP2C19 genotype correlated significantly with levels (P < 0.001): poor metabolizers (*2/*2) had the highest concentrations (8.73 ± 2.22), normal (*1/*1) and intermediate were in the therapeutic range (∼3.2 µg/mL), and rapid metabolizera had subtherapeutic levels (1.65 ± 3.21). Median levels in *1/*2 and *2/*2 were 1.9- and 5.3-fold higher than in rapid metabolizers. Hepatotoxicity, defined as ALT/AST ≥5× ULN or ≥3× ULN with symptoms or hyperbilirubinemia, occurred in 28.4% and was significantly associated with supratherapeutic levels; toxicity correlated more strongly with drug exposure than with CYP2C19 genotype alone. Multivariate analysis identified genotype (P < 0.001) and dose (P = 0.0021) as key determinants of drug levels, whereas age, gender, and weight were not significant. This prospective study shows a strong link between CYP2C19 genotype and voriconazole exposure in children, supporting genotype-guided dosing with therapeutic drug monitoring and highlighting the need for ancestry-informed precision dosing.