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

Abstract

Brivaracetam (BRV) is a high-affinity synaptic vesicle protein 2A ligand developed for the treatment of uncontrolled partial-onset seizures. The present phase I, open-label, two-way crossover study was designed to assess the effect of rifampin on the pharmacokinetics of BRV and its hydroxy (BRV-OH), acid (BRV-AC), and hydroxy acid (BRV-OHAC) metabolites. Twenty-six healthy subjects received BRV (150-mg single oral dose) either alone or following 5 days of rifampin 600 mg/day. BRV and its metabolites were examined for their plasma profiles and urinary excretion. Pharmacokinetic modeling was developed to estimate the rate constants of the various metabolic routes. Parallel in vitro assays were conducted to characterize the hydrolysis of BRV to BRV-AC as well as to identify any potential effect of rifampin on the hydrolysis reaction. Rifampin did not significantly affect the maximum plasma concentration (C max ) of BRV, but decreased its area under the curve (AUC) by 45%. In addition, rifampin significantly increased the AUC of BRV-OH (+109%), decreased the AUC of BRV-AC (253%), but had little effect on BRV-OHAC (210%). In vitro assays showed that the major urinary metabolite BRV-AC (33% of the dose) was likely to be formed by amidase EC 3.5.1.4. In vitro data indicated that the enzyme was not significantly inhibited nor induced by rifampin. Modeling confirmed that all of the observed changes in vivo were secondary to the induction of the CYP2C19-mediated hydroxylation of BRV to BRV-OH (3.7-fold increase in the rate constant).

Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years

“…Exposures to the three inactive metabolites appeared similar to those found in healthy adults, albeit the hydroxylation ratio was somewhat higher in children with epilepsy (18 vs 9% [28]), at least partly due to background therapy with enzyme-inducing AEDs.…”

Progress report on new antiepileptic drugs: A summary of the Thirteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIII)

“…In summary, in healthy subjects, the drug is rapidly and completely absorbed from the gastrointestinal tract, is <20% bound to plasma proteins, and is eliminated with a half‐life of approximately 9 h, partly by hydrolysis to the inactive carboxylic acid metabolite (the predominant metabolic pathway) and partly by cytochrome P450 (CYP)2C19–dependent hydroxylation. The enzyme responsible for the main biotransformation pathway was recently identified as amidase EC 3.5.1.4 …”

“…Coadministration with carbamazepine, phenytoin, and phenobarbital has been found to decrease brivaracetam exposure by 26%, 21%, and 19%, respectively, without significant effects on response . However, brivaracetam exposure was decreased by 45% when the drug was coadministered with the potent inducer enzyme rifampicin, which may require dose adjustment …”

Relative Bioavailability and Bioequivalence of Brivaracetam 10 mg/mL Oral Solution and 50‐mg Film‐Coated Tablet

“…It is completely absorbed orally (96.8% urinary excretion in mass balance study), shows no food effect, binds weakly to plasma proteins (17.5%), has an apparent volume of distribution corresponding to total body water, and has a plasma half‐life of approximately 9 hours . The major metabolic pathway of brivaracetam involves transformation of the amide function into a carboxylic acid by non‐CYP‐dependent enzyme amidase EC 3.5.1.4, and a second pathway involves CYP2C19‐mediated hydroxylation of the propyl side chain …”