Population Pharmacokinetic Modeling of Oxcarbazepine and Its Active Metabolite 10-Monohydroxy Derivative to Inform Dosing in Children with Obesity.

BACKGROUND: Oxcarbazepine (OXZ) is an antiepileptic drug whose pharmacological effect is primarily mediated by its active metabolite, 10-monohydroxy derivative (MHD). OXZ is approved for use in adults and children older than 2 years with an age- and body weight-tiered dosing recommendation, but dosing guidance for children with obesity is lacking. OBJECTIVE: This work aimed to assess the dosing requirements of OXZ in children with obesity to support label extension. METHODS: Two multicenter studies (NCT01431326 and NCT02993861) were conducted in patients receiving standard-of-care OXZ therapy. Participants ≥ 2 years of age with a body mass index ≥ 95th percentile were classified as obese. Plasma concentrations were measured by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. Nonlinear mixed effects modeling was performed using NONMEM 7.4 to characterize the population pharmacokinetics of OXZ and MHD simultaneously. Simulations were performed to compare MHD systemic exposure in children ≥ 2 years of age with and without obesity. RESULTS: One hundred study participants with a median (range) age of 9 years (44 days-20.90 years) contributed 425 plasma concentrations of OXZ (n = 212) and MHD (n = 213). Fifty-two percent of the participants had obesity. A one-compartment joint parent-metabolite model with linear input-output and bi-directional transformation between OXZ and MHD best characterized the pharmacokinetics. Body size was the only covariate affecting pharmacokinetics, and a fat-free mass-based metric termed pharmacokinetic weight (PKWT) best characterized that effect allometrically. Simulation results revealed that the current dosing regimen of OXZ can produce comparable exposure of MHD in children ≥ 2 years of age with and without obesity. CONCLUSION: A model-informed analysis confirms that the current pediatric dosing regimen of OXZ applies to children in general, regardless of their obesity status.