Brivaracetam: a novel antiepileptic drug for focal-onset seizures

Brivaracetam (BRV), the n-propyl analogue of levetiracetam (LEV), is the latest antiepileptic drug (AED) to be licensed in Europe and the USA for the adjunctive treatment of focal-onset seizures with or without secondary generalization in patients aged 16 years or older. Like LEV, BRV binds to synaptic vesicle protein 2A (SV2A), but BRV has more selective binding and a 15- to 30-fold higher binding affinity than LEV. BRV is more effective than LEV in slowing synaptic vesicle mobilization and the two AEDs may act at different binding sites or interact with different conformational states of the SV2A protein. In animal models, BRV provides protection against focal and secondary generalized seizures and has significant anticonvulsant effects in genetic models of epilepsy. The drug undergoes first-order pharmacokinetics with an elimination half-life of 7–8 h. Although BRV is metabolized extensively, the main circulating compound is unchanged BRV. Around 95% of metabolites undergo renal elimination. No dose reduction is required in renal impairment, but it is recommended that the daily dose is reduced by one-third in hepatic dysfunction that may prolong half-life. BRV has a low potential for drug interactions. The efficacy and tolerability of adjunctive BRV in adults with focal-onset seizures have been explored in six randomized, placebo-controlled studies. These showed significant efficacy outcomes for doses of 50–200 mg/day. The most common adverse events reported were headache, somnolence, dizziness, fatigue and nausea. Patients who develop psychiatric symptoms with LEV appear to be at risk of similar side effects with BRV, although preliminary data suggest that these issues are likely to be less frequent and perhaps less severe. As with all AEDs, a low starting dose and slow titration schedule help to minimize side effects and optimize seizure control and thereby quality of life.

[1]  M. Brodie,et al.  Brivaracetam-induced elevation of carbamazepine epoxide levels: A post-hoc analysis from the clinical development program , 2018, Epilepsy Research.

[2]  J. V. van Gerven,et al.  Pharmacological interactions between brivaracetam and ethanol in healthy males , 2017, Journal of psychopharmacology.

[3]  C. Wasterlain,et al.  Acute and long‐term effects of brivaracetam and brivaracetam–diazepam combinations in an experimental model of status epilepticus , 2017, Epilepsia.

[4]  F. Rosenow,et al.  Postmarketing experience with brivaracetam in the treatment of epilepsies: A multicenter cohort study from Germany , 2017, Epilepsia.

[5]  M. Bacher,et al.  Real-life experience with brivaracetam in 101 patients with difficult-to-treat epilepsy—A monocenter survey , 2017, Seizure.

[6]  F. Rosenow,et al.  Treatment of refractory and super-refractory status epilepticus with brivaracetam: A cohort study from two German university hospitals , 2017, Epilepsy & Behavior.

[7]  C. Brandt,et al.  Health-related quality of life in double-blind Phase III studies of brivaracetam as adjunctive therapy of focal seizures: A pooled, post-hoc analysis , 2017, Epilepsy & Behavior.

[8]  J. Wade,et al.  Brivaracetam population pharmacokinetics in children with epilepsy aged 1 month to 16 years , 2017, European Journal of Clinical Pharmacology.

[9]  M. Wood,et al.  Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein , 2017, Epilepsia.

[10]  Tao Chen,et al.  The adverse event profile of brivaracetam: A meta-analysis of randomized controlled trials , 2017, Seizure.

[11]  M. Brodie,et al.  Pharmacokinetic interaction of brivaracetam on carbamazepine in adult patients with epilepsy, with and without valproate co-administration , 2016, Epilepsy Research.

[12]  M. Brodie,et al.  Tolerability, safety, and efficacy of adjunctive brivaracetam for focal seizures in older patients: A pooled analysis from three phase III studies , 2016, Epilepsy Research.

[13]  Francesco Brigo,et al.  Efficacy and tolerability of brivaracetam compared to lacosamide, eslicarbazepine acetate, and perampanel as adjunctive treatments in uncontrolled focal epilepsy: Results of an indirect comparison meta-analysis of RCTs , 2016, Seizure.

[14]  Sheridan M. Hoy Brivaracetam: A Review in Partial-Onset (Focal) Seizures in Patients with Epilepsy , 2016, CNS Drugs.

[15]  E. Ben-Menachem,et al.  Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies , 2016, Neurology.

[16]  V. Biton,et al.  Safety and tolerability of adjunctive brivaracetam as intravenous infusion or bolus in patients with epilepsy , 2016, Epilepsia.

[17]  P. Kwan,et al.  Safety, tolerability, and seizure control during long‐term treatment with adjunctive brivaracetam for partial‐onset seizures , 2016, Epilepsia.

[18]  A. Stockis,et al.  Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus , 2016, Epilepsia.

[19]  A. Scheen,et al.  Effect of Rifampin on the Disposition of Brivaracetam in Human Subjects: Further Insights into Brivaracetam Hydrolysis , 2016, Drug Metabolism and Disposition.

[20]  M. Silvestrini,et al.  Brivaracetam add-on for refractory focal epilepsy , 2016, Neurology.

[21]  M. Wood,et al.  Brivaracetam: Rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment , 2016, Epilepsia.

[22]  F. Andermann,et al.  Brivaracetam in Unverricht‐Lundborg disease (EPM1): Results from two randomized, double‐blind, placebo‐controlled studies , 2016, Epilepsia.

[23]  Richard E Carson,et al.  Brivaracetam, a selective high‐affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action , 2016, Epilepsia.

[24]  M. Esguerra,et al.  Brivaracetam augments short‐term depression and slows vesicle recycling , 2015, Epilepsia.

[25]  M. Sperling,et al.  A randomized, double‐blind, placebo‐controlled, multicenter, parallel‐group study to evaluate the efficacy and safety of adjunctive brivaracetam in adult patients with uncontrolled partial‐onset seizures , 2015, Epilepsia.

[26]  S. Borghs,et al.  An open-label, prospective, exploratory study of patients with epilepsy switching from levetiracetam to brivaracetam , 2015, Epilepsy & Behavior.

[27]  A. Gambardella,et al.  Brivaracetam: review of its pharmacology and potential use as adjunctive therapy in patients with partial onset seizures , 2015, Drug design, development and therapy.

[28]  C. You,et al.  Adjunctive brivaracetam for patients with refractory partial seizures: A meta-analysis of randomized placebo-controlled trials , 2015, Epilepsy Research.

[29]  Xuefeng Wang,et al.  The efficacy and safety of brivaracetam at different doses for partial-onset epilepsy: a meta-analysis of placebo-controlled studies , 2015, Expert Opinion on Pharmacotherapy.

[30]  M. Habibi,et al.  Epilepsy and women's health , 2015 .

[31]  P. Rolan,et al.  Brivaracetam and carbamazepine interaction in healthy subjects and in vitro , 2015, Epilepsy Research.

[32]  Philippe Ryvlin,et al.  Epilepsy: new advances , 2015, The Lancet.

[33]  D. Kaski,et al.  Advances in the diagnosis and management of epilepsy in adults , 2015 .

[34]  V. André,et al.  Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons , 2014, CNS neuroscience & therapeutics.

[35]  N. Fauchoux,et al.  Interaction between brivaracetam (100 mg/day) and a combination oral contraceptive: A randomized, double‐blind, placebo‐controlled study , 2014, Epilepsia.

[36]  M. Sperling,et al.  Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double‐blind, placebo‐controlled trial , 2014, Epilepsia.

[37]  P. Kwan,et al.  Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double‐blind, randomized, placebo‐controlled, flexible‐dose trial , 2014, Epilepsia.

[38]  P. Ryvlin,et al.  Adjunctive brivaracetam in adults with uncontrolled focal epilepsy: Results from a double‐blind, randomized, placebo‐controlled trial , 2014, Epilepsia.

[39]  P. Rolan,et al.  Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women , 2013, Journal of clinical pharmacology.

[40]  Y. Horsmans,et al.  Brivaracetam Disposition in Mild to Severe Hepatic Impairment , 2013, Journal of clinical pharmacology.

[41]  W. van Paesschen,et al.  Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb, randomized, controlled trial , 2013, Epilepsia.

[42]  J D Norrie,et al.  Patterns of treatment response in newly diagnosed epilepsy , 2012, Neurology.

[43]  M. Gillard,et al.  Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. , 2011, European journal of pharmacology.

[44]  J. French,et al.  Adjunctive brivaracetam for refractory partial-onset seizures , 2010, Neurology.

[45]  D. Margineanu,et al.  Anti‐convulsive and anti‐epileptic properties of brivaracetam (ucb 34714), a high‐affinity ligand for the synaptic vesicle protein, SV2A , 2008, British journal of pharmacology.

[46]  R. Kaminski,et al.  SV2A protein is a broad-spectrum anticonvulsant target: Functional correlation between protein binding and seizure protection in models of both partial and generalized epilepsy , 2008, Neuropharmacology.

[47]  M. Sargentini-Maier,et al.  Pharmacokinetics and Metabolism of 14C-Brivaracetam, a Novel SV2A Ligand, in Healthy Subjects , 2008, Drug Metabolism and Disposition.

[48]  D. Truong,et al.  Brivaracetam is superior to levetiracetam in a rat model of post-hypoxic myoclonus , 2007, Journal of Neural Transmission.

[49]  P. Rolan,et al.  The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males. , 2007, British journal of clinical pharmacology.

[50]  P. Kwan,et al.  Early identification of refractory epilepsy. , 2000, The New England journal of medicine.

[51]  M. Feany,et al.  The synaptic vesicle protein SV2 is a novel type of transmembrane transporter , 1992, Cell.

[52]  R. Scheller,et al.  SV2, a brain synaptic vesicle protein homologous to bacterial transporters. , 1992, Science.

[53]  S. Irie,et al.  Brivaracetam single and multiple rising oral dose study in healthy Japanese participants: influence of CYP2C19 genotype. , 2014, Drug metabolism and pharmacokinetics.

[54]  P. Rolan,et al.  The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men. , 2008, British journal of clinical pharmacology.