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. 2025 Nov 17.
doi: 10.1007/s40262-025-01579-0. Online ahead of print.

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

Jaydeep Sinha  1 , Kanecia Zimmerman  2   3 , Stephen J Balevic  2   3   4 , Chi Hornik  2   3 , William J Muller  5 , Mobeen Rathore  6 , Marisa Meyer  7   8 , Yaron Finkelstein  9 , Amira Al-Uzri  10 , Arpita Lakhotia  11 , Stuart Goldstein  12 , Jia-Yuh Chen  13 , Ravinder Anand  13 , Daniel Gonzalez  14   15 ; Best Pharmaceuticals for Children Act–Pediatric Trials Network Steering Committee
Collaborators, Affiliations

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

Jaydeep Sinha et al. Clin Pharmacokinet. .

Abstract

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.

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Conflict of interest statement

Declarations. Conflict of Interest: The authors have no relevant conflicts of interest to disclose. Disclosures: JS's affiliation reflects the institution with which he was associated at the time this work was performed. SB receives support from the NIH and the Childhood Arthritis and Rheumatology Research Alliance, has done consulting work for UCB and Rutgers University, and serves on an NIH Data and Safety Monitoring Board. DG receives support from the Eunice Kennedy Shriver NICHD (R01HD096435, R01HD102949, R01HD113201, and HHSN275201000003I) and other sponsors for drug development in adults and children ( https://dcri.org/about-us/conflict-of-interest/ ). DG is an Editorial Board member of Clinical Pharmacokinetics. DG was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Availability of Data and Material: To help expand the knowledge base for pediatric medicine, the PTN is pleased to share data from its completed and published studies with interested investigators. For requests, please contact PTN-Program-Manager@dm.duke.edu. Ethics Approval: The AED01 study was approved by the Duke Health Institutional Review Board (IRB) under IRB number Pro0007092, and the POP01 study was approved under IRB number Pro00029638. Consent to Participate: Informed consent and assent, when applicable, were obtained from all participants enrolled in the studies that facilitated the collection of oxcarbazepine data. Consent for Publication: Not applicable. Code Availability: The NONMEM code for the final population PK model is provided in the electronic supplementary material (see ESM2). Authors’ Contributions: Participated in research design: JS, KZ, SB, and DG. Performed the research: JS, KZ, SB, CH, WM, MR, MM, YF, AA-U, AL, SG, J-YC, RA, and DG. Performed the data analysis: JS and DG. Wrote or contributed to the writing of the manuscript: JS, KZ, SB, CH, WM, MR, MM, YF, AA-U, AL, SG, J-YC, RA, and DG.

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