Abstract

Purpose: Eslicarbazepine acetate (ESL) is a once-daily antiepileptic drug (AED) that is converted to eslicarbazepine, the primary active metabolite of ESL, after oral administration. A population pharmacokinetic (PK) model for eslicarbazepine was developed and the influence of selected covariates and concomitant antiepileptics was investigated.

Methods: Multiple ESL doses of 400-1200 mg administered once daily were studied. Modeling was performed with full-profile and sparse data from 224 subjects in eleven Phase 1 studies (4240 concentrations) and 815 subjects in three Phase 3 studies (Studies 2093-301, 2093-302, and 2093-304; 1725 concentrations).

Results: A 1-compartment model with first-order absorption and elimination reasonably fit these data. Estimated basal eslicarbazepine apparent clearance (CL/F) was 2.43 L/h, with lower (33.8%) eslicarbazepine 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 with body weight of 34 or 140 kg, a CrCL of 115.7 mL/min, and not receiving concomitant AEDs relative to the same subject with body weight of 70 kg. Concomitant administration of phenobarbital/phenobarbital-like metabolic inducers (phenytoin, primidone) resulted in higher (19.6%) eslicarbazepine apparent distribution volume (V/F) compared to subjects administered no other AEDs. Female subjects had a slightly lower (16.15%) eslicarbazepine V/F compared to male subjects. The V/F increases with increasing body weight and is predicted to be 47.7, 51.4, and 56.2 L in a hypothetical female subject with a body weight of 62, 70, or 81 kg, and 56.9, 61.3, and 67.1 L for a male subject at the same body weights.

Conclusions: This modeling supported individual subject eslicarbazepine exposure estimation for Phase 3 population PK/PD efficacy analyses.

American Association of Pharmaceutical Scientists (AAPS), San Antonio, Texas, November 2013

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