title: Effect of gemfibrozil on the metabolism of brivaracetam in vitro and in human subjects.
abstract: Brivaracetam (BRV) is a new high-affinity synaptic vesicle protein 2A ligand in phase III for epilepsy. Initial studies suggested that the hydroxylation of BRV into BRV-OH is supported by CYP2C8. Other metabolic routes include hydrolysis into a carboxylic acid derivative (BRV-AC), which could be further oxidized into a hydroxy acid derivative (BRV-OHAC). The aim of the present study was to investigate the effect of gemfibrozil (CYP2C9 inhibitor) and its 1-O-β-glucuronide (CYP2C8 inhibitor) on BRV disposition both in vivo (healthy participants) and in vitro (human liver microsomes and hepatocytes). In a two-period randomized crossover study, 26 healthy male participants received a single oral dose of 150 mg of BRV alone or at steady state of gemfibrozil (600 mg b.i.d). Gemfibrozil did not modify plasma and urinary excreted BRV, BRV-OH, or BRV-AC. The only observed change was a modest decrease (approximately -40%) in plasma and urinary BRV-OHAC. In human hepatocytes and/or liver microsomes, gemfibrozil potently inhibited the hydroxylation of BRV-AC into BRV-OHAC (K(I) 12 μM) while having a marginal effect on BRV-OH formation (K(I) ≥153 μM). Gemfibrozil-1-O-β-glucuronide had no relevant effect on either reaction (K(I) >200 μM). In conclusion, gemfibrozil did not influence the pharmacokinetics of BRV and its hydroxylation into BRV-OH. Overall, in vitro and in vivo data suggest that CYP2C8 and CYP2C9 are not involved in BRV hydroxylation, whereas hydroxylation of BRV-AC to BRV-OHAC is likely to be mediated by CYP2C9.
authors.affiliation: UCB Pharma, Chemin du Foriest, Braine-l'Alleud B-1420, Belgium. Jean-marie.nicolas@ucb.com
authors.forename: J-M
authors.initials: JM
authors.lastname: Nicolas
authors.forename: H
authors.initials: H
authors.lastname: Chanteux
authors.forename: M
authors.initials: M
authors.lastname: Rosa
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: A
authors.initials: A
authors.lastname: Stockis
mesh_terms: D000927:Anticonvulsants / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018592:Cross-Over Studies; D004347:Drug Interactions; D015248:Gemfibrozil / Q000494:pharmacology*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011760:Pyrrolidinones / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D000960:Hypolipidemic Agents; D011760:Pyrrolidinones; D015248:Gemfibrozil; C482793:brivaracetam