Eslicarbazepine Acetate (BIA 2-093)

Abstract

Summary: Eslicarbazepine acetate (ESL) [(S)-(Ϫ)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide], formerly known as BIA 2-093, is a novel central nervous system (CNS)-active compound with anticonvulsant activity. It behaves as a voltage-gated sodium channel (VGSC) blocker and is currently under clinical development for the treatment of epilepsy and bipolar disorder. ESL shares with carbamazepine and oxcarbazepine the dibenzazepine nucleus bearing the 5-carboxamide substitute, but is structurally different at the 10,11-position. This molecular variation results in differences in metabolism, preventing the formation of toxic epoxide metabolites such as carbamazepine-10,11 epoxide. In pharmacokinetic studies in humans, ESL was rapidly and extensively metabolized to eslicarbazepine (S-licarbazepine), which is responsible for pharmacological activity. ESL has been tested in patients with refractory partial-onset seizures and was found to be efficacious and well tolerated. Monotherapy studies in adult epileptic patients and add-on studies in epileptic children are in the planning process. The efficacy and safety data appear to be very promising considering the refractory nature of the epileptic population enrolled in studies to date. Results of ongoing phase III studies in adult epileptic patients are expected to be available in 2007 and are required to define the position of ESL in the therapy of patients with epilepsy.

Evaluation of neurotoxic and neuroprotective pathways affected by antiepileptic drugs in cultured hippocampal neurons

“…In fact, at least in humans this AED is readily converted to S-Lic and R-Lic (Almeida and Soares-da-Silva, 2007). Regarding the fact that OXC is a minor metabolite of ESL in humans, OXC accounts for less than 5% of metabolized ESL, and it is unlikely that high concentrations of OXC as those used in this study will reach the brain.…”

“…ESL is structurally different at the 10,11-position, and consequently, it is not metabolized to CBZ-10,11-epoxide and, therefore, it is not susceptible to enzyme induction or autoinduction (Bialer, 2006). Moreover, ESL is a once-daily AED (Almeida and Soares-da-Silva, 2007) that is rapidly absorbed and undergoes extensive first-pass metabolism, in humans (Almeida et al, 2005) and mice (Alves et al, 2007), to its main active metabolite, eslicarbazepine (S-Lic), which is responsible for approximately 95% of total systemic drug exposure, and to a lesser extent to Rlicarbazepine (R-Lic) and OXC, (Almeida et al, 2005). Our group previously demonstrated that ESL is less toxic to cultured neurons than CBZ and OXC, namely at high concentrations (0.3 mM).…”

Enantioselective HPLC‐UV method for determination of eslicarbazepine acetate (BIA 2‐093) and its metabolites in human plasma

“…Eslicarbazepine acetate (ESL) [S-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide], previously known as BIA 2-093, is a novel chiral drug presently completing phase III clinical trials, as add-on therapy in refractory partial epilepsy, and undergoing phase II clinical trials, as monotherapy in partial epilepsy and in bipolar disorder (Almeida and Soares-da-Silva, 2007). ESL is chemically related to CBZ and OXC (Benes et al, 1999).…”

Ion Channels as Drug Targets in Central Nervous System Disorders

“…9) is an AED second-generation to carbamazepine. It showed efficacy in several animal seizure models both electrically (MES) and chemically (pentetrazole, bicuculline, picrotoxin, 4-aminopyridine) evoked [51]. [52].…”