Brivaracetam (UCB 34714)

Abstract

Brivaracetam (UCB 34714) is chemically related to levetiracetam (LEV, Keppra). It possesses a binding affinity for the synaptic vesicle protein 2A (SV2A) ten-fold above that of LEV and also shows an ability to inhibit Na+ channels. This correlates with a higher potency in suppressing epileptiform responses in vitro and a more potent and complete suppression of different seizure types in animals with an acquired or genetic epilepsy. Brivaracetam has been tested in a comprehensive safety pharmacology, toxicology, developmental toxicology, and genotoxicity program. It is of low acute toxicity, target organ for toxic effects is the hepatobiliary tract. Carcinogenicity studies are ongoing. Human pharmacology studies have shown that brivaracetam has a half-life of 8 h and nearly complete bioavailability. Brivaracetam is primarily metabolized via hydrolysis of the acetamide group and CYP2C8-mediated hydroxylation. Its metabolites are not pharmacologically active. Excretion of over 95% of the dose, including metabolites, occurs renally within 72 h. Healthy volunteer studies demonstrated a favorable tolerability profile. Treatment emergent adverse events were mild to moderate, mostly of CNS origin, and resolved within 24 hrs, with decreasing incidence after repeated intake. Drug-drug interaction studies with high dose of brivaracetam (400 mg/d) showed a dose-dependent increase of carbamazepine-epoxide levels. No significant interaction with low doses of phenytoin was observed at the same high dose levels of brivaracetam, and only a moderate pharmacokinetic interaction with an oral contraceptive, without impact on hormonal levels or ovulation, was observed. The pharmacokinetic profile of brivaracetam is unaltered in elderly subjects or those with impaired renal function. Clearance of brivaracetam is reduced in patients with hepatic insufficiency. In the photoparoxysmal response model in patients with photosensitive epilepsy brivaracetam was effective at all tested doses (10 - 80 mg) in reducing or abolishing EEG discharges evoked by a photic stimulus. Phase 2 studies in patients with refractory partial onset seizures have recently been completed.