Abstracts

Rationale: Brivaracetam (BRV) is a selective and high-affinity synaptic vesicle protein 2A ligand. BRV has been previously reported to be orally bioavailable with rapid absorption and an elimination t_1/2 of about 8h. BRV shows linear dose-proportional pharmacokinetics and its disposition is minimally affected by hepatic or renal impairment. The present in vitro work was performed to further characterize BRV with emphasis on risks of pharmacokinetic drug-drug interactions (DDI) and properties that drive blood-brain barrier permeability. Methods: The metabolic routes of BRV have been characterized using human liver microsomes, human cytochromes P-450 (CYPs) and recombinant amidases. BRV and its major metabolites have been tested for potential inhibitory activity against a large panel of transporters, CYPs (both reversible and irreversible inhibition) and epoxide hydrolase (EH). Various antiepileptic drugs (eg felbamate, phenytoin, carbamazepine, valproic acid, lamotrigine, zonisamide, phenobarbital) were tested for their ability to impair the in vitro metabolism of BRV in human liver fractions. The ability of BRV to induce CYPs was evaluated in human hepatocytes measuring CYP marker activities. Active transport of BRV has been assessed using cells or vesicle membranes expressing MDR1 (P-gp), MRP1 and MRP2. Passive diffusion permeability was investigated in Caco-2 cells. Results: BRV is metabolically cleared by ω-1 hydroxylation of the propyl side-chain, hydrolysis of the butyramide side-chain, and combination of both. The reactions mainly involve CYP2C19, amidase (E.C.3.5.1.4) and CYP2C9, respectively. BRV did not produce any significant inhibition of the investigated CYPs or transporters. Some modest inhibition of EH was observed. None of the tested AEDs affected the in vitro metabolism of BRV. BRV was found without relevant CYP inducing potential. BRV did not act as a substrate of the tested membrane transporters. BRV showed a high passive diffusion permeability, close to that of phenytoin and benzodiazepine. Conclusions: BRV did not significantly impair drug metabolizing enzymes or transporters, and thus is unlikely to cause clinically significant pharmacokinetic DDI. Equally, BRV pharmacokinetics should not be affected by coadministered drugs. Metabolic reaction phenotyping suggested that BRV disposition should be modestly affected by genetic polymorphism. Finally, the high passive diffusion of BRV and the lack of efflux transport should translate in a fast entry into brain tissues. All these properties are well aligned with the clinical data accumulated so far. UCB supported