Pharmacokinetic-Pharmacodynamic Modeling and Simulation to Predict Efficacy Outcomes With Eslicarbazepine Acetate 800 mg Once Daily as Monotherapy for Partial-Onset Seizures

Authors: Sunkaraneni S, Passarell JA, Ludwig EA, Pitner J, Grinnell T, Blum D
Conference: ACoP
Keywords: efficacy outcomes, eslicarbazepine acetate, pharmacodynamic modeling, seizures
Division: Cognigen

Introduction

  •  Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED), approved as adjunctive treatment for partial-onset seizures (POS) in the USA, Europe, and Canada, and as monotherapy for POS in the USA.
  •  Following oral dosing, ESL is rapidly and extensively metabolized to the active metabolite, eslicarbazepine,1 which is thought to act primarily by preferentially stabilizing the inactivated state of voltage-gated sodium channels.2
  • Conversion to ESL monotherapy (1200 mg and 1600 mg QD) has been studied in two Phase 3 studies (093-045 and 093-046) in patients with POS whose seizures were previously not adequately controlled while taking either one or two AEDs.3-5 Conversion to ESL monotherapy at both the doses examined (1200 mg and 1600 mg) was found to be effective (superior to a historical control) and well tolerated.3-5
  • The FDA-recommended dose range for ESL maintenance is 800–1600 mg QD.6 For patients on ESL monotherapy, a maintenance dose of 800 mg QD should generally be considered for patients who are unable to tolerate a dose of 1200 mg QD.6 Here, pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to estimate the efficacy of conversion of patients to ESL monotherapy (800 mg QD; this dose was not examined as a maintenance dose in the Phase 3 studies). The model was also used to predict efficacy outcomes in patients converting from either one or two AEDs (approximately 70% of patients were taking one AED during the baseline period5).

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

By Julie A Passarell, Elizabeth A Ludwig