In Vitro Pharmacokinetic Profile of Brivaracetam (BRV) Reveals Low Risk of Drug-Drug Interaction (DDI) and Unrestricted Brain Permeability (P4.276)

OBJECTIVE: To characterize BRV for the risks of DDI and properties driving its permeability through the blood-brain barrier. BACKGROUND: BRV is a selective and high-affinity synaptic vesicle protein 2A ligand. BRV is orally bioavailable with rapid absorption, a t½ of 9h, linear pharmacokinetics, and a disposition minimally affected by hepatic or renal impairment. DESIGN/METHODS: BRV metabolism has been characterized using human liver microsomes, human cytochromes P-450 (CYPs), and recombinant amidases. BRV and its major metabolites have been tested for inhibitory activity against transporters, CYPs and epoxide hydrolase (EH). Various antiepileptic drugs (AEDs; eg felbamate, phenytoin, carbamazepine, valproate, lamotrigine, zonisamide, phenobarbital) were tested for their ability to impair the in vitro metabolism of BRV. The potential of BRV to induce CYPs was evaluated in human hepatocytes. Active transport of BRV was assessed using cells and vesicle membranes expressing MDR1 (P-gp), MRP1, and MRP2. Cell permeability was investigated in Caco-2 cells. RESULTS: BRV is metabolized through ω-1 hydroxylation of the propyl side-chain, hydrolysis of the butyramide side-chain, and combination of both. The reactions mainly involve CYP2C19, amidase, and CYP2C9, respectively. BRV did not produce significant inhibition of CYPs or transporters. Some modest inhibition of EH was observed. None of the tested AEDs affected the in vitro metabolism of BRV. BRV did not significantly induce CYP nor demonstrate substrate activity against the tested transporters. BRV showed a high passive diffusion permeability, similar to phenytoin and benzodiazepine. CONCLUSIONS: BRV did not significantly impair metabolizing enzymes or transporters, and is unlikely to cause clinically significant DDI. BRV pharmacokinetics should not be affected by coadministered drugs. Metabolic reaction phenotyping suggested that BRV disposition should be modestly affected by genetic polymorphism. The high permeability of BRV and lack of efflux transport should translate into fast brain tissue entry. Study Supported by: UCB Disclosure: Dr. Chanteux has received personal compensation for activities with UCB Pharma as an employee. Dr. Kervyn has received personal compensation for activities with UCB Pharma as an employee. Dr. Gerin has received personal compensation for activities with UCB Pharma as an employee. Dr. Rosa has received personal compensation for activities with UCB Pharma as an employee. Dr. Latour has received personal compensation for activities with UCB Pharma as an employee. Dr. Stockis has received personal compensation for activities with UCB Pharma as an employee. Dr. Nicolas has received personal compensation for activities with UCB Pharma as an employee.