Effect of eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers Denise Milovan a , Luis Almeida b,c , Myroslava K. Romach a , Teresa Nunes b , José Francisco Rocha b , Marta Sokowloska a , Edward M. Sellers a , Patrício Soares-da-Silva b,d, ⁎ a Kendle Early Stage, Toronto, ON, Canada b Department of Research and Development, BIAL-Portela & Company, S.A., Sao Mamede do Coronado, Portugal c Health Sciences Section, University of Aveiro, Aveiro, Portugal d Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal abstract article info Article history: Received 23 December 2009 Received in revised form 19 April 2010 Accepted 20 April 2010 Available online 18 June 2010 Keywords: Antiepileptic drugs Cognition Eslicarbazepine acetate Oxcarbazepine Psychomotor performance The results of two single-blind studies conducted to evaluate the cognitive and psychomotor effects of eslicarbazepine acetate and oxcarbazepine following single and repeated administration in healthy volunteers are reported. The cognitive and psychomotor evaluation consisted of several computerized and paper-and-pencil measures. Eslicarbazepine acetate and oxcarbazepine had similar overall cognitive profiles and did not cause clinically relevant cognitive impairment. The incidence of adverse events was lower with eslicarbazepine acetate than with oxcarbazepine. © 2010 Published by Elsevier Inc. 1. Introduction Antiepileptic drugs (AEDs) interact with neurotransmitter receptors or ion channels to decrease membrane excitability, thus contributing to a reduction in brain seizure activity. One pharmacological target is the voltage-gated sodium channel (VGSC) and its blockade is the proposed mechanism of action for several AEDs, such as carbamazepine (CBZ), oxcarbazepine (OXC), lamotrigine, and phenytoin [1]. Eslicarbazepine acetate (ESL) is a novel VGSC blocker [2,3] recently approved in Europe for use as adjunctive therapy for refractory partial- onset seizures. ESL is chemically related to CBZ and OXC. ESL shares with CBZ and OXC the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position [3]. Following oral administration, ESL is rapidly and extensively metabo- lized to eslicarbazepine, the drug entity responsible for the pharmaco- logical effect [4]. In randomized, double-blind, placebo-controlled phase III studies in adult patients with uncontrolled partial-onset seizures despite treatment with one or two concomitant AEDs [5,6] or one to three concomitant AEDs [7], ESL at once-daily doses of 800 and 1200 mg was generally well tolerated and significantly decreased seizure frequency compared with placebo. AEDs usually exhibit a dose-dependent effect on cognitive function- ing. Because AEDs are the major therapeutic modality for patients with epilepsy, comparison of the adverse cognitive effects of AEDs is important [8]. Despite effective anticonvulsant properties, OXC has been associated with several central nervous system-related adverse events including cognitive symptoms [9–11]. This study compared the pharmacodynamic effects of a single 900-mg oral dose of ESL or OXC and the effects of repeated administration of two oral doses of ESL (800 and 1200 mg administered once daily [QD]) and oral doses of OXC (300 and 600 mg administered twice daily [BID]). 2. Methods 2.1. Study design Two single-blind studies were conducted to evaluate the cognitive and psychomotor effects of oral doses of ESL and OXC in healthy volunteers. Each study consisted of a single-dose phase (phase A) followed by a multiple-dose phase (phase B) comprising three periods (Fig. 1). In phase A, subjects were administered a single 900-mg dose of ESL or OXC (day 1). In phase B, subjects were administered: placebo in period 1 (days 2–8); ESL 800 mg QD or OXC 300 mg BID in period 2 (days 9–15); and ESL 1200 mg QD or OXC 600 mg BID in period 3 (days 16–22). The dosage regimens for the current study were defined according to the results of the ESL phase III studies [5–7] and the recommended dosage of OXC [10,12] as adjunctive therapy for Epilepsy & Behavior 18 (2010) 366–373 ⁎ Corresponding author. Department of Research and Development, BIAL-Portela & Company, S.A., À Av. da Siderurgia Nacional, 4745-457 S Mamede do Coronado, Portugal. Fax: + 351 22986 6192. E-mail address: psoares.silva@bial.com (P. Soares-da-Silva). 1525-5050/$ – see front matter © 2010 Published by Elsevier Inc. doi:10.1016/j.yebeh.2010.04.022 Contents lists available at ScienceDirect Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh