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 six decades. Previous reports indicated neonates, infants, and toddlers/preschoolers had higher risk of valproate hepatotoxicity than adults. However, dosing recommendations for those less than ten years of age are lacking. To decipher clinical puzzles, physiologically based pharmacokinetics (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 impacts of CYP2C9 and UGT2B7 on dispositions of VPA and 4‐ene‐VPA across age groups. Optimal VPA dosing for each pediatric age group was also predicted and objectively judged by ensuring VPA efficacy and avoiding 4‐ene‐VPA hepatotoxicity. The study revealed UGT2B7 ontogeny was quite influential on VPA clearance even in neonates and small children. Intrinsic clearance of CYP2C9 was the most prominent determinant for AUCs of VPA and 4‐ene‐VPA in infants, and toddlers and preschoolers, reflecting higher hepatotoxicity risk due to noxious 4‐ene‐VPA accumulation in these groups. The ontogeny‐based PBPK approach complements conventional allometric methods in dosing estimation for the young by providing more mechanistic insight of the processes changing with age. The established ontogeny‐based PBPK approach for VPA therapy deserves further corroboration by real‐world therapeutic data to affirm its clinical applicability.

Pharmacokinetic and pharmacodynamic principles: unique considerations for optimal design of neonatal clinical trials

“…As a result, dose selection based on scaling often overestimates doses in neonates and infants as they experience rapid maturational changes and variability in pharmacokinetics. Huang et al (23) provide an example demonstrating the importance of including the maturation of key drug metabolizing enzymes of valproic acid, CYP2C9 and UGT2B7, on dose selection. The authors show that except for Clark's rule, most conventional scaling methods would lead to under-or overdosing in neonates and infants.…”

“…The authors show that except for Clark's rule, most conventional scaling methods would lead to under-or overdosing in neonates and infants. For instance, in comparison with physiologically-based pharmacokinetic (PBPK) model approach, which is a tool that uses a mechanistic understanding of drug disposition in the body (including enzyme ontogeny) to predict drug exposures (discussed further in the paragraph below), body surface dosing of valproic acid in infants would lead to almost an inappropriate 2-fold increase in C max (23).…”

Sources of pharmacokinetic and pharmacodynamic variability and clinical pharmacology studies of antiseizure medications in the pediatric population

“…leveraged PBPK modeling to investigate the impact of enzyme ontogeny on hepatotoxic risk and proposed dosing regimens that minimize this serious adverse effect in this age group. 86 A PBPK model investigated cannabidiol exposure in healthy and hepatically impaired adults and children. 87 This supports the applicability of PBPK modeling to successfully predict drug exposures when sparse clinical data is available, and future applications include assessing cannabidiol‐drug or cannabidiol‐disease interactions in special populations.…”