Physiologically-Based and Population Pharmacokinetic Modeling and Simulation to Support Dose Selection and Study Design for Eslicarbazepine Acetate (ESL) Adjunctive Therapy in Infants with Partial Onset Seizures (POS)

Objective: To develop a modeling and simulation strategy to inform dose selection and design of a clinical trial in infants aged 1 month to 4 years. Background: The safety and efficacy of adjunctive ESL has been studied in adult and pediatric populations down to 2 years of age with population pharmacokinetic (PPK) models of the primary active ESL metabolite eslicarbazepine. Design/Methods: A modeling and simulation strategy with sequential PPK extrapolation (‘top down’ approach) and physiologically based PK (PBPK) prediction (‘bottom up’ approach) was designed. Results: A previously developed 1-compartment pediatric PPK model for eslicarbazepine was enhanced to include literature-based maturation functions for renal and extrarenal elimination. Allometric scaling by weight was used to modify apparent clearance and volume of distribution. Concomitant antiepileptic use was included in the model. PPK model-based stochastic simulations of prior data from pediatric and adult patients estimated steady-state exposures in infants aged 1– Conclusions: An integrated PPK and PBPK modeling and simulation strategy provided a quantitative basis to support ESL dose selection and study design for a planned clinical trial in infants, without conducting a separate PK study. Study Supported by: Sunovion Pharmaceuticals Inc. Disclosure: Dr. Sunkaraneni has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee. Dr. Ludwig has received personal compensation for activities with Cognigen Corporation – a subsidiary of Simulations Plus for scientific analysis. Dr. Bihorel has received personal compensation for activities with Cognigen Corporation as an employee. Dr. Bihorel has received research support from Sunovion Pharmaceuticals Inc. Dr. Morris has received personal compensation for activities with Cognigen Corporation. Dr. Morris has received research support from Sunovion Pharmaceuticals Inc. Dr. Hopkins has received personal compensation for activities with Sunovion Pharmaceuticals Inc as an employee. Employee of Sunovion Pharmaceuticals Inc.,,,,,, Dr. Fiedler-Kelly has received personal compensation for activities with Cognigen Corporation as a employee. Dr. Fiedler-Kelly has receive research support from Sunovion Pharmaceuticals Inc. Dr. Blum has received personal compensation for activities with Sunovion Pharmaceuticals Inc. as an employee.