Abstracts

Rationale: In two phase III trials of ESL monotherapy (2093-045 and -046) in patients with partial-onset seizures, monotherapy was superior to historical controls. Data from these studies are used to examine the relationships between eslicarbazepine exposure and selected efficacy endpoints. ESL is not approved for monotherapy use. Methods: Both trials included 8-wk baseline, 2-wk titration, and 16-wk double-blind ESL (1600mg or 1200mg QD; 10-wk monotherapy) treatment periods. Eslicarbazepine exposures in individual patients were calculated using a population PK model. Seizures were recorded by the patients; patients exited the study if ≥1 of five criteria (signifying worsening seizure control) were met. Predictive models were developed through data analysis, base structural modeling and covariate evaluation, and then validated for concordance between simulated and observed data. Results: Data from 296 patients (83% Caucasian, 51% male) were included (some subjects did not contribute to all endpoints). Median age: 38 yrs; one baseline AED: 67%; two AEDs: 33%. Patients had 15 seizures (median) during baseline (range 4-91). Predictive models were developed to describe the relationship between eslicarbazepine exposure and time to: study exit; 6^th seizure during double-blind ESL treatment (including AED taper period); and 3^rd seizure during ESL monotherapy. Higher eslicarbazepine C_min (minimum concentration) and use of one baseline AED were associated with lower risk of study exit (Table 1). For each 1000ng/mL increase in C_min, the risk of study exit decreased by 9.5%. During the 16-wk treatment period, a relationship was apparent between eslicarbazepine exposure and time to 6^th seizure (but not 1^st or 3^rd); no single exposure measure was a significant predictor (Table 2). During the 10-wk monotherapy period, 76.4% of patients had ≥3 seizures. When exposure measures were grouped into quartiles, a relationship was apparent between exposure and time to 1^st, 3^rd and 6^th seizures. Higher eslicarbazepine C_min, lower baseline seizure frequency and black race were significantly associated with lower risk of a 3^rd seizure (Table 1). The risk of a 3^rd seizure (at median C_min) was 10% lower with ESL 1600mg versus 1200mg (not tested statistically). The probability of seizure freedom was not related to eslicarbazepine exposure during the 10 wks of monotherapy. However, eslicarbazepine C_min was a statistically significant predictor of seizure freedom during the last 4 wks of monotherapy. The predicted probability of seizure freedom during the last 4 wks of monotherapy (at median C_min) was 0.16 and 0.21 for ESL 1200mg and 1600mg. Conclusions: Plasma eslicarbazepine concentration was a weak predictor of time to study exit, time to 3^rd seizure, and probability of seizure freedom during the last 4 wks of monotherapy, and did not predict overall seizure freedom following conversion to ESL monotherapy. Eslicarbazepine plasma concentration monitoring is of little value during ESL monotherapy; the current findings do not support making dose adjustments on the basis of plasma eslicarbazepine levels.