Population Pharmacokinetics and Exposure-Response Analyses of Eslicarbazepine Acetate Efficacy and Safety in Monotherapy of Partial-Onset Seizures.

Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug (AED) indicated for partial-onset seizures (POS). ESL pharmacokinetics (PK) and exposure-response analyses were supported by 2 phase 3 conversion to ESL (1200, 1600 mg) monotherapy studies. The PK model development included 10 phase 1-2 studies (ESL 600-1200 mg daily). Seizure diaries were completed daily; subjects exited if seizures worsened. Exposure-response models were developed for time to study exit, probability of seizure freedom, time to first occurrence of dizziness, headache, and nausea; serum sodium levels were explored. A 1-compartment model with first-order absorption/elimination described ESL PK. Clearance and distribution volume were significantly related to body weight and sex. Higher eslicarbazepine minimum concentration (Cmin ) and use of 1 baseline AED were associated with significantly lower risk of study exit, whereas eslicarbazepine Cmin was a significant predictor of seizure freedom during the last 4 weeks of monotherapy. Eslicarbazepine exposure and the time to first occurrence of adverse events were not related. A shallow negative relationship described the relationship between change from baseline in serum sodium level and eslicarbazepine exposure. Eslicarbazepine apparent clearance and distribution volume estimates were similar to those reported for ESL adjunctive therapy. Dose adjustment based on body weight was not required. The time to study exit and probability of seizure freedom during the last 4 weeks of monotherapy were weakly related to eslicarbazepine exposure. Because the first occurrence of adverse events or hyponatremia were also not significantly related to eslicarbazepine exposure, dose adjustment using plasma eslicarbazepine concentrations is not supported.