Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug. ESL is converted to eslicarbazepine after oral administration. Three phase III randomized controlled trials in patients with partial-onset seizures (2093-301, -302 and -304) showed that adjunctive ESL was generally well tolerated (Rogin et al. Epilepsy Curr 2014;14 [Suppl. 1]:209). The current analysis evaluates the relationship between eslicarbazepine exposure and incidence of adverse events (AEs) during adjunctive therapy. Methods: Each trial comprised an 8-wk baseline period and a 14-wk double-blind period (2-wks titration, 12-wks maintenance). ESL doses ranged from 400mg to 1200mg QD. Eslicarbazepine exposures in individual patients were calculated using a population PK model. Data for the double-blind period were analyzed. Predictive models for the relationship between exposure and AE incidence were developed via data analysis, base structural modeling and evaluation of covariates, and were validated for concordance between simulated and observed data. Results: Data from 1152 patients were analyzed (80% Caucasian, 52% male; age 16-75yrs; body weight 34-135kg). Dizziness, somnolence and headache occurred in 15%, 12% and 11%, respectively. The derived models showed that the incidence of each AE was ~two-fold higher with an initial dose of 800mg ESL vs. 400mg. After accounting for initial ESL dose, eslicarbazepine AUC_0-24 (area under the concentration-time curve) was significantly associated with occurrence of dizziness and headache; somnolence was related to C_max (maximum concentration). Higher exposure was related to lower AE incidence. The final models predicted the following: risk of dizziness higher in females vs. males and in North America (NA), Latin America (LA) and ‘Rest of World' (ROW) vs. Europe; risk of somnolence higher in LA vs. Europe, NA and ROW; risk of dizziness headache and somnolence lower at higher body weight. Carbamazepine use during baseline was associated with greater risk of dizziness but lower risk of somnolence; lamotrigine use increased risk of dizziness; levetiracetam and valproic acid use had no effect. Reductions in serum sodium levels were proportional to eslicarbazepine exposure; the relationship was shallow and linear. An increase in ESL dose of 400mg is predicted to reduce serum sodium levels by 0.68mmol/L. Conclusions: Together with efficacy modeling data (Harvey et al. AES 2014, submitted), these results suggest that an optimal risk-benefit profile is achieved with an initial dose of 400mg ESL, followed by titration to 800-1200mg. Use of an initial dose of 800mg to achieve greater efficacy carries a greater risk of AEs. After accounting for the initial dose of ESL, there is no ascending relationship between eslicarbazepine exposure and incidence of frequent AEs; the risk of hyponatremia is only weakly dose-dependent. Monitoring of eslicarbazepine plasma concentrations to determine the therapeutic range would therefore not be useful.