Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED). Orally dosed ESL is rapidly metabolized to eslicarbazepine (Almeida et al. Eur J Clin Pharmacol 2008;64:267-73), which acts by stabilizing the inactivated state of voltage-gated sodium channels. Two recent phase (ph) III studies of ESL monotherapy for partial-onset seizures found that ESL had superior efficacy to historical controls, with a safety/tolerability profile consistent with that reported for adjunctive ESL. This report describes development of a population PK model for eslicarbazepine during ESL monotherapy. ESL is not approved for use as monotherapy. Methods: Data were derived from two ph III monotherapy studies and 10 ph I studies (ESL 600-1600mg QD). Plasma samples were collected for the ph I and ph III studies (12-21 and 1-5 samples per person, respectively) for 24 hours after ESL dosing. Eslicarbazepine concentrations were determined using liquid chromatography with tandem mass spectrometry. A previously developed PK model (without covariate effects) was applied to eslicarbazepine concentration-time data and further refined. Exponential error models described inter-individual variability (IIV) in the absorption rate constant (k_a), apparent oral clearance (CL/F) and apparent volume of distribution (V/F). Two additive plus constant coefficient of variation (CCV) error models accounted for differences in residual variability in ph I, and a CCV error model for ph III data. Univariate forward selection-backward elimination analysis identified predictors of PK variability, and simulation-based visual predictive check methodology assessed concordance between simulated and observed data. Results: The analysis population comprised 493 patients (80% Caucasian; 56% male; median age 36 years; median BMI 26kg/m²). The PK profile of eslicarbazepine was 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 absorption half-life (t_1/2) were 2.56L/h, 62.6L and 0.65h, respectively. Body weight was a significant predictor of V/F and CL/F (higher CL/F and V/F at higher body weights). There were also statistically significant gender-based differences (lower CL/F and V/F in females). However, the overall impact of body weight and gender on exposure was predicted to be small and not clinically relevant. Neither age nor race had a significant impact on CL/F or V/F. Baseline concomitant AED use did not affect eslicarbazepine concentrations over time during ESL monotherapy. Conclusions: This analysis established a PK model for eslicarbazepine during ESL monotherapy. Differences in body weight, gender, age or race do not appear to necessitate dose adjustments. Although the ESL doses used for monotherapy (1200mg, 1600mg) were higher than for adjunctive treatment, CL/F and V/F were similar. Absorption t_1/2 was higher than previously estimated for adjunctive treatment.