CYP2C19 Phenotype and Body Weight-Guided Voriconazole Initial Dose in Infants and Children after Hematopoietic Cell Transplantation.
Abstract
Prophylactic voriconazole use is recommended for children undergoing hematopoietic cell transplantation (HCT). Dosing considerations are essential, due to the narrow therapeutic window of voriconazole. Known covariates do not sufficiently explain the large interindividual pharmacokinetic (PK) variability of voriconazole. Moreover, knowledge of voriconazole PK for age <2 years is limited. We investigated genetic and clinical covariate associations with voriconazole interindividual PK variability and subsequently simulated dosing regimens in children. This study was conducted as part of a single-institution, phase I study of intravenous voriconazole therapy for children undergoing HCT. We conducted a population PK analysis and tested covariate effects on voriconazole PK, including 67 genetic variants and clinical variables. We analyzed plasma voriconazole and N-oxide metabolite concentrations from 58 children <21 years of age (including 12 children <2 years of age). A two-compartment parent mixed linear/nonlinear model best described our data. The CYP2C19 phenotype and body weight were significant covariates (P < 0.05 for both). Our model performance for age <2 years was comparable to that for other age groups. Simulation of the ...Continue Reading
References
Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults.
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