Abstracts

Rationale: In a phase II placebo-controlled, adjunctive therapy study in adult patients with partial-onset seizures eslicarbazepine acetate (ESL) 800 and 1200 mg/day once-daily (QD) was found to be efficacious and well tolerated. However, the same dose given twice-daily (BID) was not significantly more efficacious than placebo (Epilepsia, 48, 497-504, 2007). The present study investigated the steady-state pharmacokinetics of QD and BID regimens of ESL and BID regimen of oxcarbazepine (Trileptal®; OXC) in healthy volunteers. Tolerability was also assessed. Methods: Single centre, open-label, randomised, three-way crossover study in 12 healthy volunteers. The study consisted of three 8-day treatment periods separated by a washout period of 10-15 days. In each treatment period the volunteers received a daily dose of either ESL (900 mg QD or 450 mg BID) or 450 mg of OXC BID. A chiral LC-MS bioanalytical method was used to quantify eslicarbazepine, (R)-licarbazepine and oxcarbazepine. Results: Eslicarbazepine was the major active entity in plasma, accounting for 94.6%, 93.9% and 81.5% of total exposure within the corresponding dosing interval (τ) at steady state (AUCss,0-τ) with ESL QD, ESL BID and OXC BID, respectively. Eslicarbazepine Cmax,ss (in µmol/L) following ESL QD (87.3) was 33% higher compared to ESL BID (65.5) and 82% higher compared to OXC BID (48.0) (Figure 1). The AUCss,0-τ (in µmol*h/L) following the last dose of an 8-day repetitive dosing was 1156, 1118 and 968 for ESL QD, ESL BID and OXC BID, respectively (Table 1). Trough plasma eslicarbazepine before the last dose was 31% lower in the ESL QD in relation to ESL BID and OXC BID (22, 32 and 32 µmol/L, respectively). The ratio eslicarbazepine plasma exposure (µmol*h/L) to daily dose (µmol) was 0.38 (1156:3037), 0.37 (1118:037) and 0.27 (968:3567) for ESL QD, ESL BID and OXC BID, respectively, which translates in a 40% increase in efficiency of ESL QD (and ESL BID) versus OXC BID to deliver their major active entity eslicarbazepine. The extent of plasma exposure to drug entities (R)-licarbazepine and oxcarbazepine after ESL QD was 72% and 61% lower than after OXC BID, respectively. Thirty, 18 and 18 treatment-emergent adverse events were reported in the OXC BID, ESL BID and ESL QD, respectively. Conclusions: In comparison to ESL BID, administration of ESL QD resulted in 33% higher peak plasma concentration (Cmax,ss) of eslicarbazepine, which may correlate with the efficacy profile reported with ESL. In comparison to OXC BID, administration of ESL QD resulted in 40% increase in the efficiency to deliver eslicarbazepine, less R-licarbazepine and less oxcarbazepine. which may relate to differences in the clinical profiles of ESL and OXC.