Eslicarbazepine Acetate Drug–Drug Interactions: Characterization Through a Model-Based Population Approach

Authors: Sunkaraneni S, Ludwig EA, Blum D, Fiedler-Kelly J
Conference: ACoP
Keywords: AED, eslicarbazepine acetate, neurology, PK
Division: Clinical Pharmacology and Pharmacometrics (CPP)

Introduction

  • Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED), approved by the US Food and Drug Administration for the treatment of partial-onset seizures (POS) as monotherapy or adjunctive therapy. ESL is approved by the European Medicines Agency as adjunctive therapy of POS in adults.
  • Following oral administration, ESL is rapidly and extensively metabolized to the active metabolite, eslicarbazepine, which accounts for approximately 95% of systemic drug exposure1,2 (the minor metabolites, oxcarbazepine [OXC] and R-licarbazepine, account for <1% and ~5%, respectively).3
    • The maximum plasma concentration (Cmax) of eslicarbazepine is reached approximately 3 hours post-dose, with steady-state being achieved after 4–5 days of QD dosing.1,2
    • Eslicarbazepine is mainly eliminated by renal excretion (unchanged or following glucuronidation).2,4
  • The effect of concomitant administration of ESL on the pharmacokinetics (PK) of phenytoin (PHT), lamotrigine (LTG), topiramate (TPM), and carbamazepine (CBZ) was investigated in four Phase I, open-label, drug-drug interaction (DDI) studies in healthy volunteers.
  • DDIs between ESL and other AEDs were further characterized using population PK models.
    • A population PK model was developed for eslicarbazepine using data from 11 Phase I studies and three Phase III studies of adjunctive ESL.
    • Population PK models for six other AEDs (CBZ, valproate [VAL], levetiracetam [LEV], phenobarbital [PB], PHT, and gabapentin [GBP]) were developed using data from the three Phase III studies of adjunctive ESL.
  • The population PK models were used to characterize the effect of concomitant AED use on PK of eslicarbazepine, and the effect of concomitant ESL on the PK of the other AEDs.

American Conference on Pharmacometrics (ACoP) Annual Meeting: October 4-7, 2015, Crystal City, VA.

By Soujanya Sunkaraneni, Elizabeth A Ludwig, David Blum, Jill Fiedler-Kelly