Abstracts

Rationale: Eslicarbazepine acetate (ESL) is an antiepileptic that is converted to eslicarbazepine after oral administration. Eslicarbazepine stabilizes the inactivated state of voltage-gated sodium channels and blocks T-type voltage-gated calcium channels. ESL was approved in 2009 by the European Medicines Agency as adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. ESL is not approved in the US. A population pharmacokinetic (PK) model was developed to assess co-administration of AEDs on PKs of eslicarbazepine following ESL dosing.Methods: 24h PK sampling data were derived from 11 ph I and 3 ph III trials, in which ESL was given at 400 1200mg once daily. A prior PK model without covariate effects (except body weight) was applied to eslicarbazepine concentration time data and further refined. Exponential error models described inter-individual variability (IIV) in k_a, CL/F and V/F and two additive plus proportional error models accounted for differences in residual variability between ph I and ph III data. The impact of concomitant AEDs on PKs of eslicarbazepine was analyzed sequentially, first by presence/absence, then, if significant, by effect of dose and/or concentration. Univariate analysis backward elimination identified predictors of PK variability, and simulation-based visual predictive check methodology assessed concordance between simulated and observed data.Results: PKs of eslicarbazepine were described by a one-compartment model with first-order absorption and elimination. All estimates had good precision, IIV was large (k_a) or moderate (CL/F, V/F) (Table 1). Residual variability was moderate (ph III) or low (ph I). Estimated base eslicarbazepine CL/F, V/F, and t_1/2 were 2.43L/h, 61.3L, and 0.296h, respectively. Co-administration of phenobarbital or phenobarbital-like metabolic inducers (PLMI; phenytoin, primidone) with ESL increased eslicarbazepine CL/F (Table 1), and resulted in a 33.8% decrease in AUC_ss compared with ESL alone, which may indicate the need for a higher ESL dose (Table 2). Co-administration of carbamazepine (CBZ) also increased eslicarbazepine CL/F, and led to a 25.1 46.8% reduction in AUC_ss (median, 30.8% at 400mg twice daily) compared with ESL alone. When administered with CBZ, ESL dose adjustment may be warranted based on the need for additional seizure control; lower doses of CBZ may be needed based on tolerability. Co-administration of phenobarbital/PLMI resulted in a 19.6% higher eslicarbazepine V/F versus ESL alone. Valproate, lamotrigine, and levetiracetam had no appreciable impact on PKs of eslicarbazepine. Eslicarbazepine CL/F increased with increasing CrCL according to a power function (Table 1).Conclusions: Co-administration of CBZ or PLMIs with ESL results in a decrease in eslicarbazepine exposure. A higher dose of ESL may be required when PLMIs are co-administered. Dose adjustment of ESL may be warranted during CBZ co-administration based on the need for additional seizure control; lower doses of CBZ may be needed based on tolerability.