Modeling and Simulation Strategy to Support Eslicarbazepine Acetate (ESL) Development in Pediatric Patients in the Treatment of Partial-Onset Seizures

Conference: ACoP


  • Eslicarbazepine acetate (ESL, Aptiom®) was FDA approved for adjunctive treatment of partial-onset seizures (POS) in adults aged 18 years and older, with subsequent approval as monotherapy.
  • A recent FDA analysis has provided evidence across antiepileptic drugs (AEDs) that exposure-response relationships are preserved between adult and pediatric subjects (aged 4 years and older) with POS.1
  • The population pharmacokinetic (PPK) modeling of Phase 1 and Phase 3 studies supporting the ESL submissions in adults was used as a basis for dose selection in pediatric patients aged 4 to 17 years.
  • Doses were selected for treating POS in pediatric subjects (aged 4 to 17 years) by targeting eslicarbazepine (primary active metabolite of ESL) exposures at levels demonstrated to be effective in adults, as per FDA analysis, and consistent with the PEACE initiative deliberations on extrapolation.2
  • A modeling and simulation strategy with sequential PPK extrapolation (‘top down’ approach) and physiologically based pharmacokinetic (PBPK) prediction (‘bottom up’ approach) considering maturation of relevant elimination pathways was designed to leverage prior data from the pediatric patients and adults to inform dose selection and design of a clinical trial in infants aged 1 month to 4 years old.
  • An overview of key steps in the modeling and simulation strategy employed in the pediatric development of ESL is provided in Figure 1.

Seventh American Conference on Pharmacometrics (ACoP), October 22-18, 2016, Bellevue, Washington

By Sebastien Bihorel, Elizabeth A Ludwig, Jill Fiedler-Kelly, Denise Morris