Brivaracetam and carbamazepine interaction in healthy subjects and in vitro

Stockis, Armel; Chanteux, Hugues; Rosa, Maria de Lurdes Pereira; Rolan, Paul

doi:10.1016/j.eplepsyres.2015.03.003

Cited by 48 publications

(34 citation statements)

References 23 publications

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“…BRV neither inhibits nor induces CYPs in a clinically relevant manner, nor does it inhibit drug transporters, and its metabolism is not affected by reference AEDs including felbamate, phenytoin, valproate, lamotrigine, zonisamide, and phenobarbital . The only noticeable finding is a modest increase in carbamazepine‐epoxide when BRV is coadministered with carbamazepine . This interaction is without safety consequences and does not require dose adjustment.…”

Section: Blood–brain Barrier Permeability and Pharmacokineticsmentioning

confidence: 96%

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Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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SUMMARYDespite availability of effective antiepileptic drugs (AEDs), many patients with epilepsy continue to experience refractory seizures and adverse events. Achievement of better seizure control and fewer side effects is key to improving quality of life. This review describes the rationale for the discovery and preclinical profile of brivaracetam (BRV), currently under regulatory review as adjunctive therapy for adults with partial-onset seizures. The discovery of BRV was triggered by the novel mechanism of action and atypical properties of levetiracetam (LEV) in preclinical seizure and epilepsy models. LEV is associated with several mechanisms that may contribute to its antiepileptic properties and adverse effect profile. Early findings observed a moderate affinity for a unique brain-specific LEV binding site (LBS) that correlated with anticonvulsant effects in animal models of epilepsy. This provided a promising molecular target and rationale for identifying selective, high-affinity ligands for LBS with potential for improved antiepileptic properties. The later discovery that synaptic vesicle protein 2A (SV2A) was the molecular correlate of LBS confirmed the novelty of the target. A drug discovery program resulted in the identification of anticonvulsants, comprising two distinct families of high-affinity SV2A ligands possessing different pharmacologic properties. Among these, BRV differed significantly from LEV by its selective, high affinity and differential interaction with SV2A as well as a higher lipophilicity, correlating with more potent and complete seizure suppression, as well as a more rapid brain penetration in preclinical models. Initial studies in animal models also revealed BRV had a greater antiepileptogenic potential than LEV. These properties of BRV highlight its promising potential as an AED that might provide broad-spectrum efficacy, associated with a promising tolerability profile and a fast onset of action. BRV represents the first selective SV2A ligand for epilepsy treatment and may add a significant contribution to the existing armamentarium of AEDs.

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Section: Blood–brain Barrier Permeability and Pharmacokineticsmentioning

confidence: 96%

“…50 The only noticeable finding is a modest increase in carbamazepine-epoxide when BRV is coadministered with carbamazepine. 57,58 This interaction is without safety consequences and does not require dose adjustment.…”

Section: Blood-brain Barrier Permeability and Pharmacokineticsmentioning

confidence: 99%

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

et al. 2016

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“…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).…”

Section: Brivaracetam [(2s)-2-[(4r)-2-oxo-4-propylpyrrolidinyl] Butanmentioning

confidence: 99%

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

Stockis

Watanabe

Scheen

et al. 2016

Drug Metabolism and Disposition

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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).

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“…6 BRV may increase plasma concentration of carbamazepineepoxide and thus warrants close monitoring for adverse effects. 28 Carbamazepine reduced the AUC of BRV by 29%. BRV 200 mg BID increased phenytoin concentration up to 20%, theoretically from weak CYP2C19 inhibition.…”

Section: Adverse Drug Reactions and Drug-drug Interactionsmentioning

confidence: 96%

“…The manufacturer suggests doubling BRV dose with concomitant rifampin . BRV may increase plasma concentration of carbamazepine‐epoxide and thus warrants close monitoring for adverse effects . Carbamazepine reduced the AUC of BRV by 29%.…”

Section: Adverse Drug Reactions and Drug‐drug Interactionsmentioning

confidence: 99%

Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures

Kappes

Hayes

Strain

et al. 2017

The Journal of Clinical Pharmacology

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Brivaracetam is an analogue of levetiracetam that is Food and Drug Administration-approved for adjunctive treatment of partial-onset seizures in patients 16 years and older. In placebo-controlled trials adjunct brivaracetam demonstrated efficacy in reducing the frequency of seizures. The most commonly reported adverse effects are somnolence, dizziness, and fatigue. Clinical trials have evaluated brivaracetam for safety and efficacy in adjunctive treatment of partial-onset seizures in patients 16 years and older for up to 16 weeks. Brivaracetam's mechanism is similar to that of levetiracetam but with greater receptor binding affinity on synaptic vesicle protein 2A and inhibitory effects on sodium channels. Clinically significant differences between these agents are undetermined. Brivaracetam is available as oral tablets, oral solution, and intravenous solution. The Food and Drug Administration-approved dose is 50 mg twice daily, and titration is not required. Brivaracetam does not need dose adjustment for renal impairment and has minimal drug-drug interactions. Current limitations of brivaracetam include lack of head-to-head trials, limited long-term safety and efficacy data, and cost. Overall, brivaracetam is a viable adjunct therapeutic option for refractory partial-onset seizures in those who have failed conventional therapies.

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Brivaracetam and carbamazepine interaction in healthy subjects and in vitro

Cited by 48 publications

References 23 publications

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment

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

Brivaracetam: An Adjunctive Treatment for Partial-Onset Seizures

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