PI-100 - PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODELING TO CHARACTERIZE THE DISPOSITION OF TOPIRAMATE IN CHILDREN WITH AND WITHOUT OBESITY USING REAL-WORLD DATA.

P. Maglalang¹, D. Gonzalez², W. Muller³, C. Hornik⁴, S. Goldstein⁵, M. Rathore⁶, J. Ford⁷, S. Balevic⁴, J. Sinha⁷, A. Edginton⁸, J. Chen⁹, R. Anand¹⁰, K. Zimmerman⁴, on behalf of the Best Pharmaceuticals for Children Act- Pediatric Trials Network Steering Commitee; ¹University of North Carolina at Chapel Hill, Chapel Hill, NC, USA, ²Duke University, Durham, USA, ³Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA, ⁴Duke University, Durham, NC, USA, ⁵Cincinnati Children's Hospital Medical Center, Cincinnati, USA, ⁶University of Florida Jacksonville Shands Medical Center, Jacksonville, FL, USA, ⁷University of North Carolina, Chapel Hill, NC, USA, ⁸University of Waterloo, Kitchener, ON, Canada, ⁹The Emmes Company, LLC, Rockville, MD, USA, ¹⁰The Emmes Company, LLC, Rockville, USA.

Background: Topiramate treats seizures in children 2 years of age and older. It is excreted primarily by the kidney and undergoes concentration-dependent and saturable binding to red blood cells (RBCs). In children, topiramate dosing is weight-based. It is unknown whether the same dosing approach can be applied to children with obesity (body mass index ≥ 95th percentile) who may have an altered glomerular filtration rate. We developed a novel PBPK model to characterize the effect of obesity on the pharmacokinetics (PK) of topiramate in children and leveraged real-world data to evaluate our model.

Methods: The Pediatric Trials Network enrolled children with and without obesity < 21 years old taking topiramate per standard of care (SOC) in two multicenter trials (NCT01431326 and NCT02993861). Topiramate plasma concentrations were measured by a validated LC-MS/MS assay. An adult PBPK model was developed by incorporating glomerular filtration, tubular reabsorption, and concentration-dependent RBC binding using PK-Sim® and MoBi® (v 10.257). The adult model was evaluated by leveraging PK data in adults from the literature. Then, the model was scaled to children, accounting for age- and obesity-related changes. The pediatric model was evaluated using data from SOC studies, involving children receiving topiramate. Simulations were then performed to characterize PK in a virtual population of children ≥ 2 years old with and without obesity.

Results: Our adult PBPK model captured observed literature data well across the dose range of 25 to 1200 mg with an average fold error of 0.98. In our evaluation of the pediatric model, 72% of 133 concentrations from 43 children (86% with obesity; median [range] 8 years [2-18] old) fell within the 90% prediction interval. Model predictions revealed that children with obesity (i.e., Class 1, 2, and 3 obesity) had lower simulated weight-normalized clearance than children without obesity (i.e., non-overweight and overweight) (Figure).

Conclusion: The PK of topiramate in children with obesity was successfully characterized using PBPK modeling and evaluated using real-world data from children taking the drug per SOC.