Physiologically Based Pharmacokinetic Modeling to Characterize the Disposition of Topiramate in Children with and without Obesity.

Topiramate (TPM) is used to treat seizures in adults and children ≥2 years. In children, TPM dosing is body weight based. It is unknown whether children with obesity may benefit from an alternative dosing strategy. We developed a novel physiologically based pharmacokinetic (PBPK) model for TPM that accounts for age- and obesity-related changes in disposition. The model was first developed and evaluated in adults before scaling to children then finally evaluated using opportunistic pharmacokinetic data from two multicenter studies where children with and without obesity ages 2-18 years received TPM per standard of care. Simulations were performed to characterize pharmacokinetic parameters and assess the current labeled dosing regimen in a virtual population of children with obesity (≥2 years). The adult PBPK model performed well when evaluated with observed literature data, resulting in an average fold error of 0.989 across the dosing range of 25-1200 mg. The pediatric data used in model evaluation included 43 children (86% with obesity; median [range], 8 [2-18] years); 71% of 134 observed concentrations fell within the 90% prediction interval for the PBPK model. PBPK based dosing simulations revealed comparable exposure (<20% difference) in children with and without obesity receiving the Topamax product label weight-tiered dose for monotherapy (weight tiered for 2 to <10 years and fixed dosing for 10 to ≤18 years) or weight-based adjunctive therapy. Comparable trough concentrations between children with and without obesity suggest the current dosing recommendations, including monotherapy and adjunctive therapy, are appropriate for children with obesity.