Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2A

Abstract

Background and purpose: Screening of 12 000 compounds for binding affinity to the synaptic vesicle protein 2A (SV2A), identified a high-affinity pyrrolidone derivative, brivaracetam (ucb 34714). This study examined its pharmacological profile in various in vitro and in vivo models of seizures and epilepsy, to evaluate its potential as a new antiepileptic drug. Experimental approach: The effects of brivaracetam and levetiracetam on epileptiform activity and seizure expression were examined in rat hippocampal slices, corneally kindled mice, audiogenic seizure-susceptible mice, maximal electroshock and pentylenetetrazol seizures in mice, hippocampal-kindled rats, amygdala-kindled rats and genetic absence epilepsy rats. Key results: Brivaracetam and levetiracetam reduced epileptiform responses in rat hippocampal slices, brivaracetam being most potent. Brivaracetam also differed from levetiracetam by its ability to protect against seizures in normal mice induced by a maximal electroshock or maximal dose of pentylenetetrazol. In corneally kindled mice and hippocampal-kindled rats, brivaracetam induced potent protection against secondarily generalized motor seizures and showed anti-kindling properties superior to levetiracetam. In amygdala-kindled rats, brivaracetam induced a significant suppression in motor-seizure severity and, contrary to levetiracetam, reduced the after-discharge at a higher dose. Audiogenic seizure-susceptible mice were protected more potently against the expression of clonic convulsions by brivaracetam than by levetiracetam. Brivaracetam induced a more complete suppression of spontaneous spike-and-wave discharges in genetic absence epilepsy rats than levetiracetam. Conclusions and implications: Brivaracetam has higher potency and efficacy than levetiracetam as an anti-seizure and antiepileptogenic agent in various experimental models of epilepsy, and a wide therapeutic index.

Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis

“…(BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (Gillard et al, 2011) that is effective in different animal models of epilepsy (Matagne et al, 2008). In patients with photosensitive epilepsy, BRV showed a dose-dependent effect in suppressing or attenuating the photoparoxysmal response (Kasteleijn-Nolst Trenite et al, 2007).…”

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

“…If seizures are not fully controlled with benzodiazepines, second-line AEDs such as phenytoin/fosphenytoin, sodium valproate, lacosamide, [3] or the SV2A AED levetiracetam (LEV) are used [4]. brivaracetam (BRV) is an analog of LEV, rationally designed to have a higher affinity and selectivity for SV2A, a protein involved in synaptic vesicle exocytosis and neurotransmitter release [5,6]. Brivaracetam chemically is a 4-npropyl analog of levetiracetam and a racetam derivative with anticonvulsant properties [7,8].…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…More generally, it will be of interest to assess the role of pharmacological modulation of SV2A in antiepileptogenesis. In this context it is noteworthy that the selective, high-affinity SV2A ligand brivaracetam shows more pronounced antiepileptogenic effects than levetiracetam in the kindling model [57].…”

“…In support of this possibility, numerous studies have demonstrated that levetiracetam counteracts the process of kindling when administrated immediately before kindling stimulation during the acquisition of kindling [14,15,[54][55][56][57]. As for valproate (see above), levetiracetam was tested using an experimental design consisting of a first phase in which drug treatment is administered before each kindling stimulation, and a second phase in which daily kindling stimulation is continued, but without drug pretreatment [14,15].…”