Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action

Eslicarbazepine acetate ( ESL ) is a once daily antiepileptic drug ( AED ) approved by the European Medicines Agency ( EMA ), the Food and Drug Administration ( FDA ) and Health Canada as an adjunctive therapy in adults with partial‐onset seizures ( POS ). In humans and in relevant animal laboratory species, ESL undergoes extensive first pass hydrolysis to its major active metabolite eslicarbazepine that represents ~95% of circulating active moieties. ESL and eslicarbazepine showed anticonvulsant activity in animal models. ESL may not only suppress seizure activity but may also inhibit the generation of a hyperexcitable network. Data reviewed here suggest that ESL and eslicarbazepine demonstrated the following in animal models: (1) the selectivity of interaction with the inactive state of the voltage‐gated sodium channel ( VGSC ), (2) reduction in VGSC availability through enhancement of slow inactivation, instead of alteration of fast inactivation of VGSC , (3) the failure to cause a paradoxical upregulation of persistent Na + current ( I NaP ), and (4) the reduction in firing frequencies of excitatory neurons in dissociated hippocampal cells from patients with epilepsy who were pharmacoresistant to carbamazepine ( CBZ ). In addition, eslicarbazepine effectively inhibited high‐ and low‐affinity hCa V 3.2 inward currents with greater affinity than CBZ . These preclinical findings may suggest the potential for antiepileptogenic effects; furthermore, the lack of effect upon K V 7.2 outward currents may translate into a reduced potential for eslicarbazepine to facilitate repetitive firing.