Abstract

Statement of Purpose, Innovation or Hypothesis: Eslicarbazepine acetate (ESL), a once-daily antiepileptic drug (AED), is converted to eslicarbazepine, the primary active metabolite of ESL, after oral administration. The population pharmacokinetics (PK) of eslicarbazepine were investigated, including assessment of covariates and concomitant antiepileptics.

Description of Methods and Materials: Multiple ESL doses (400-1200 mg) administered once-daily were studied. Modeling was performed with data from eleven Phase 1 (224 subjects/4240 concentrations) and three Phase 3 studies (815 subjects/1725 concentrations).

Data and Results: A 1-compartment model with first-order absorption and elimination reasonably fit these data. Estimated eslicarbazepine apparent clearance (CL/F) was 2.43 L/h, with lower (33.8%) area under the concentration-time curve at steady-state (AUCss) with concomitant administration of phenobarbital / phenobarbital-like metabolic inducers (phenytoin, primidone) or carbamazepine (range: 25.1% – 34.4% for carbamazepine doses of 200 mg twice daily to 400 mg three times daily). Eslicarbazepine CL/F increases with increasing creatinine clearance (CrCL); a hypothetical subject with an estimated CrCL of 80 or 50 mL/min, and body weight of 70 kg will have a higher (7.5% and 17.8%) eslicarbazepine AUCss as compared to a hypothetical subject with the median CrCL of 115.7 mL/min and body weight of 70 kg. Eslicarbazepine CL/F increases in proportion to body weight, with AUCss 24.3% higher and 27.5% lower for a hypothetical subject weighing 34 or 140 kg versus 70 kg, a CrCL of 115.7 mL/min, and not receiving concomitant AEDs. Concomitant administration of phenobarbital / phenobarbital-like metabolic inducers (phenytoin, primidone) resulted in higher (19.6%) eslicarbazepine apparent distribution volume (V/F). Females had lower (16.15%) eslicarbazepine V/F compared to males; a difference not expected to be clinically relevant. The V/F increases with increasing weight and is predicted to be 47.7, 51.4, and 56.2 L in a hypothetical female subject with a weight of 62, 70, or 81 kg, and 56.9, 61.3, and 67.1 L for a male subject with equivalent weight.

American College of Clinical Pharmacy (ACCP), Atlanta, Georgia, September 2014

By Elizabeth A Ludwig, Soujanya Sunkaraneni, Jill Fiedler-Kelly, Qiang Lu, Gary Maier, David Blum, Jahnavi Kharidia