Pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine at steady state in healthy volunteers *Christian Elger, †Meir Bialer, ‡Am  ılcar Falc~ ao, §¶Manuel Vaz-da-Silva, §Teresa Nunes, #Lu  ıs Almeida, and §¶Patr  ıcio Soares-da-Silva *Department of Epileptology, University of Bonn, Bonn, Germany; †Institute for Drug Research, Faculty of Medicine, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem, Israel; ‡Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal; §BIAL – Portela & Cª, S.A., S. Mamede do Coronado, Portugal; ¶Faculty of Medicine, University of Porto, Porto, Portugal; and #Health Sciences Department, University of Aveiro, Aveiro, Portugal 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 lM) fol- lowing ESL QD (87.3) was 33.3% higher (p < 0.05) com- pared 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–s (in lmol 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 (lmol h/L) to ESL daily-dose (lmol) 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 expo- sure 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–s ) when com- pared 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. KEY WORDS: Eslicarbazepine acetate, Oxcarbazepine, Pharmacokinetics, Once-daily, Twice-daily, Tolerability, Healthy volunteers. Eslicarbazepine acetate (ESL) was initially described as endowed with distinctive anticonvulsant properties (Benes et al., 1999; Ambrosio et al., 2002) and later approved by the European Medicines Agency (EMA) as once-daily adjunctive therapy in adults with partial-onset seizures, with or without secondary generalization. ESL is structurally dis- tinct from carbamazepine (CBZ) and oxcarbazepine (OXC), although the three compounds are dibenz[b,f]azepine deriv- atives (Benes et al., 1999). This molecular distinction results in differences in pharmacokinetics, pharmacody- namics, and metabolism (Hainzl et al., 2001). Unlike CBZ, ESL is not metabolized to carbamazepine-10,11-epoxide and is not susceptible to metabolic autoinduction (Almeida et al., 2009; Bialer & Soares-da-Silva, 2012). The distinctive anticonvulsant properties of ESL and eslicarbazepine (Benes et al., 1999; Ambrosio et al., 2002) are characterized by a wider (1.5- to 2.5-fold) protective- index in the mouse maximal electroshock and the 6 Hz psychomotor tests when compared to CBZ (Pires et al., 2011; Torrao et al., 2011). Although on its own ESL prefer- entially blocks voltage-gated sodium channels (VGSCs) in rapidly firing neurons (Bonifacio et al., 2001), the in vivo effects of ESL may be limited to its extensive conversion to eslicarbazepine. Mechanistically, however, it is important to underscore that the affinity of eslicarbazepine for VGSCs in the resting state is about 15- to 5-fold lower than that of CBZ, OXC, and (R)-licarbazepine, a feature that may translate into an enhanced inhibitory selectivity of eslicarbazepine for rapidly firing “epileptic” neurons over Accepted May 1, 2013; Early View publication June 12, 2013. Address correspondence to Patr  ıcio Soares-da-Silva, Department of Research and Development, BIAL,  A Av. da Siderurgia Nacional, 4745- 457 S. Mamede do Coronado, Portugal. E-mail: psoares.silva@bial.com Trial Registration: ClinicalTrials.gov: BIA-2093-110 NCT01679002. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy 1453 Epilepsia, 54(8):1453–1461, 2013 doi: 10.1111/epi.12242 FULL-LENGTH ORIGINAL RESEARCH