Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers

Summary Purpose Investigate the pharmacokinetics of once‐daily ( QD ; 900 mg) and twice‐daily ( BID ; 450 mg) regimens of eslicarbazepine acetate ( ESL ) and BID (450 mg) regimen of oxcarbazepine ( OXC ) at steady state in healthy volunteers. Methods Single‐center, open‐label, randomized, three‐way (n = 12) crossover studies in healthy volunteers. Key Findings Mean eslicarbazepine C max,ss (in μ m ) following ESL QD (87.3) was 33.3% higher (p < 0.05) compared to ESL BID (65.5) and 82.1% higher (p < 0.05) compared to OXC BID (48.0). The mean area under the curve ( AUC ) ss,0–τ (in μmol h/L) following the last dose of an 8‐day repeated dosing was 1156.3, 1117.6, and 968.4 for ESL QD , ESL BID , and OXC BID , respectively. The ratio eslicarbazepine plasma exposure (μmol h/L) to ESL daily‐dose (μmol) was 0.381 (1156.3:3037.3), 0.368 (1117.6:3037.3), and 0.271 (968.4:3567.6) for ESL ‐ QD , ESL ‐ BID , and OXC ‐ BID , respectively, which translates into a 40.6% increase in the ability of ESL ‐ QD compared to OXC ‐ BID to deliver into the plasma their major active entity eslicarbazepine. The extent of plasma exposure to ESL minor metabolites: (R)‐licarbazepine and oxcarbazepine after ESL ‐ QD was 71.5% and 61.1% lower, respectively, than after OXC ‐ BID . Twenty, 24 and 38 treatment emergent adverse events were reported with ESL ‐ QD , ESL ‐ BID , and OXC ‐ BID , respectively. Significance ESL ‐ QD resulted in 33.3% higher peak plasma concentration (C max,ss ) of eslicarbazepine and similar extent of plasma exposure ( AUC ss,0–τ ) when compared to ESL ‐ BID , which may contribute to the efficacy profile reported with once‐daily ESL . In comparison to OXC ‐ BID , administration of ESL ‐ QD resulted in 40.6% increase in the delivery of eslicarbazepine into the plasma as well as a significantly lower systemic exposure to (R)‐licarbazepine and oxcarbazepine.