Abstracts

Rationale: In two phase III trials of ESL monotherapy (2093-045 and -046) in patients with POS, the incidence of adverse events (AEs) was found to be related to ESL dose. Higher ESL doses lead to greater eslicarbazepine exposure (Falcao et al. CNS Drugs 2012;26:79-91). The current analysis evaluates the relationship between eslicarbazepine exposure and the time to first onset of AEs, and the relationship between exposure and serum sodium levels, in the monotherapy setting. ESL is not approved for monotherapy use. Methods: Both trials included an 8-week baseline period, a 2-week titration period, and 16 weeks of double-blind ESL (1600 or 1200mg QD). Eslicarbazepine exposures in individual patients were calculated using a population pharmacokinetic model. The relationships between eslicarbazepine exposure and the time to first occurrence of the three most common AEs (dizziness, headache and nausea), and serum sodium levels were examined. Results: Data from 302 patients (83% Caucasian, 50% male) were included in the analysis of time to first AE. Median age was 38 years. AEDs used at entry by ≥15% of subjects were: carbamazepine, valproic acid, levetiracetam and lamotrigine. Data from 299 patients were included in the analysis of serum sodium; patient demographics were similar to the above. Dizziness, headache and nausea occurred in 22%, 23% and 10% of patients, respectively. There was no significant relationship between eslicarbazepine exposure and the time to first occurrence of these AEs (Table 1). The median baseline serum sodium concentration was 140mmol/L (range 126−152mmol/L). In most patients there was no notable trend in serum sodium levels over time. The changes from baseline were similar for ESL 1200mg and 1600mg QD, while linear regression analysis showed a shallow negative relationship between serum sodium level and eslicarbazepine exposure. At the highest exposure, the predicted reduction in serum sodium from baseline was <3mmol/L, which is not clinically significant. Conclusions: Higher exposure to eslicarbazepine was not related to the time to first occurrence of dizziness, headache or nausea. This may be because AEs tended to occur soon after initiation of ESL, including during the first 2 weeks of the study (the titration period) when ESL dose and eslicarbazepine exposure would have been low. With increasing eslicarbazepine exposure, the reduction in serum sodium levels predicted by the model would not be clinically relevant, even at the highest exposures. However, individual patients may have significantly low sodium levels, regardless of exposure. Since there was no significant relationship between eslicarbazepine exposure and hyponatremia or the first occurrence of AEs, monitoring plasma eslicarbazepine concentrations would not be useful for making decisions regarding hyponatremia, or for determining the optimal dose of ESL monotherapy.