Effect of Gemfibrozil on the Metabolism of Brivaracetam In Vitro and in Human Subjects

Abstract

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-␤-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 M) while having a marginal effect on BRV-OH formation (K i >153 M). Gemfibrozil-1-O-␤-glucuronide had no relevant effect on either reaction (K i >200 M). 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.

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

“…[9][10][11][12][13]. As per literature review, no LC-MS/MS method was available for determination of brivaracetam alone from rabit plasma, the validated method was successfully applied for the determination of Tmax, Cmax, AUC0→t and AUC0→α using rabbits as test animals.…”

“…Brivaracetam chemically is a 4-npropyl analog of levetiracetam and a racetam derivative with anticonvulsant properties [7,8]. Literature survey pharmacokinetics and metabolism of 14C-brivaracetam, metabolism studies of brivaracetam and gemfibrozil, clinical trials of adjunctive brivaracetam for refractory partial-onset seizures, identification of drug metabolites in human plasma or serum integrating metabolite prediction, by LC-HRMS methods are reported for the drug [9][10][11][12][13]. To best of our knowledge, no published LC-MS/MS-based methods for the pharmacokinetic study of brivaracetam in healthy rabbits.…”

Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII)

“…Brivaracetam is weakly bound to plasma proteins (~17.5%), and its half-life is about 8 h. Brivaracetam is renally excreted following extensive metabolism, primarily by hydrolysis and to a lesser extent by CYP-dependent hydroxylation Sargentini-Maier et al, 2008). The main isoenzyme responsible for hydroxylation was later shown to be CYP2C19 (Nicolas et al, 2012;Stockis et al, 2014b). Consistent with this, only 5-8% unchanged brivaracetam is excreted in urine (Rolan et al, 2008), along with pharmacologically inactive metabolites (von Rosenstiel et al, 2009).…”

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

“…Secondary pathways include CYP2C19-mediated hydroxylation of BRV to brivaracetam hydroxy metabolite (BRV-OH; 16% of dose in urine) Stockis et al, 2014) and CYP2C9-mediated hydroxylation of BRV-AC to the hydroxy acid metabolite (BRV-OHAC; Fig. 1; 15% of dose in urine Nicolas et al, 2012;Stockis et al, 2015). All three metabolites of BRV are pharmacologically inactive (UCB data on file).…”