Physiologically based mechanistic insight into differential risk of valproate hepatotoxicity between children and adults: A focus on ontogeny impact.

ABSTRACT: The anticonvulsant valproic acid (VPA) despite complex pharmacokinetics has been in clinical use for nearly 6 decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than 10 years of age are lacking. To decipher clinical puzzles, physiologically-based pharmacokinetic (PBPK) models of VPA and its hepatotoxic metabolite 4-ene-VPA were constructed and simulated with particularly integrated information of drug-metabolizing enzyme ontogeny. Adult and pediatric PK data of VPA (n = 143 subjects) and 4-ene-VPA (n = 8 subjects) collected from previous reports were used for model development and validation. Sensitivity analyses were performed to characterize ontogeny impac

SUBMITTER: Huang YT 

PROVIDER: S-EPMC10725263 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature