Abstracts

Rationale: Eslicarbazepine acetate (ESL) is a novel, antiepileptic drug (AED) in development. ESL and oxcarbazepine (OXC) active metabolites (S-licarbazepine [eslicarbazepine] and R-licarbazepine) are formed in the periphery and cross the blood-brain barrier (BBB) to reach the voltage-gated sodium channel. It is unknown whether the metabolites differ in ability to cross the BBB and how the cerebrospinal fluid (CSF) concentrations correlate with their plasma concentrations. Methods: Healthy volunteers were randomized to one of 2 treatment groups (ESL group or OXC group). Subjects were titrated over 3 days to target doses of 1200 mg QD of ESL or 600 mg BID of OXC, and treated from day 4 to day 9. Blood samples and metabolites level determinations were collected on Day 1 pre-dose and Day 9 pre-dose and 30 min, 1, 1.5, 2, 3, 4, 6, 8, 12, 16 and 24 h post-dose (16 and 24 h post-dose only in the ESL group). CSF samples for the ESL and OXC groups and metabolites level determinations were collected on Day 9 pre-dose and 30 min, 1, 2, 4, 6, 8, 12, 16 and 24 h post-dose (16 and 24 h post-dose only in the ESL group). Concentrations of eslicarbazepine, R-licarbazepine and OXC in plasma and CSF were measured and pharmacokinetic parameters determined. Tolerability of ESL and OXC was assessed. This study was approved by the applicable ethics committee. Results: Fourteen subjects were randomized (7 ESL; 7 OXC) and treated. In the ESL group, the relative plasma exposure to eslicarbazepine, R-licarbazepine and OXC was 93.84%, 5.20% and 0.96% in plasma and 91.96%, 7.13% and 0.91% in CSF, respectively. In the OXC group, results were 78.06%, 18.47% and 3.47% in plasma and 76.42%, 21.36% and 2.22% in CSF, respectively. The apparent half-life of eslicarbazepine in plasma was approximately 16 hrs. and in CSF was approximately 24 hrs. The incidence of common treatment emergent adverse events is shown in Table 1. Conclusions: In this study, in comparison to OXC, administration of eslicarbazepine acetate resulted in more eslicarbazepine, less R-licarbazepine and less OXC in plasma and CSF. The CSF half-life of eslicarbazepine was longer than the plasma apparent half-life; this has implications for dosing interval and may support once-daily dosing