Abstracts

Rationale: Brivaracetam, currently in Phase III development for epilepsy, is a novel high-affinity synaptic vesicle protein 2A (SV2A) ligand also displaying inhibitory activity at neuronal voltage-dependent sodium channels. Levetiracetam (Keppra^®)and brivaracetam have different profiles in preclinical models of epilepsy. In the present study protective activity of brivaracetam was assessed in the 6 Hz model of partial epilepsy, which has been increasingly used in the discovery of novel antiepileptic drugs. Finally, the protective activity and safety profile of brivaracetam was compared with older antiepileptic drugs and levetiracetam. Methods: Corneal stimulation (0.2 ms-duration monopolar pulses at 6 Hz for 3 s) was delivered by a constant-current device (ECT Unit 57800; Ugo Basile, Comerio, Italy) to male NMRI mice. A fixed current intensity (44 mA) was used to challenge the animals after i.p. pretreatment with different doses of antiepileptic drugs: carbamazepine (15 min), phenytoin (120 min), valproate (15 min), levetiracetam (60 min) and brivaracetam (30 min). This allowed constructing dose-response curves and calculating ED₅₀ values (a dose predicted to protect 50% of tested animals against 6 Hz seizures). CNS adverse effects were assessed in the rotarod test and TD₅₀ values were determined (a dose predicted to produce motor impairment in 50% of tested animals). A therapeutic index (TI) was calculated for each compound as the ratio between TD₅₀ and ED₅₀ values. Results: Brivaracetam displayed dose-dependent protection against 6 Hz seizures with an ED₅₀ of 4.4 mg/kg. Potency of brivaracetam was several fold higher than the potency of older antiepileptic drugs and levetiracetam: carbamazepine (ED₅₀ = 10.1 mg/kg), levetiracetam (ED₅₀ = 19.2 mg/kg), phenytoin (ED₅₀ = 21.2 mg/kg) and valproate (ED₅₀ = 141 mg/kg). Brivaracetam (TI = 44) shared with levetiracetam (TI = 116) a therapeutic index markedly higher than older antiepileptic drugs: phenytoin (TI = 6.1), diazepam (TI = 5.6), carbamazepine (TI = 3.6) and valproate (TI = 2.1). Conclusions: Brivaracetam demonstrates protective activity in the 6 Hz model of partial epilepsy with potency superior to older antiepileptic drugs, including levetiracetam. The profile of brivaracetam in this model also indicates a marked separation between doses producing anticonvulsant and undesired effects.