[ARTICLE] Brivaracetam: a novel antiepileptic drug for focal-onset seizures . – Full Text

Abstract

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.

Introduction

Epilepsy is the most common chronic neurological condition. Globally, 65 million individuals are affected¹ and the diagnosis is made in an estimated 2.4 million people each year.² Despite the availability of over 14 new antiepileptic drugs (AEDs) during the past three decades, repeated outcome analyses show that >30% fail to achieve prolonged seizure freedom with medical treatment.^3–5 The introduction of novel agents is, therefore, welcome. Brivaracetam (BRV) is the latest 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. This article discusses the pharmacological properties of BRV, its performance in regulatory studies, details of its efficacy, tolerability and safety profiles and its place in everyday clinical practice.

Mechanisms of action and activity profile in animal models

BRV was discovered during a large-scale programme aimed at optimizing pharmacodynamic activity at a novel molecular AED target.⁶ It is the n-propyl analogue of levetiracetam (LEV; Figure 1), which acts as a high-affinity ligand for synaptic vesicle protein 2A (SV2A). SV2A is an integral transmembrane glycoprotein expressed in neurons and endocrine cells, which is involved in the modulation of synaptic vesicle exocytosis and neurotransmitter release.⁷ It also appears to have an important role in epileptogenesis, since SV2A deficiency in transgenic mice leads to increased seizure vulnerability.⁶

Figure 1. Chemical structures of levetiracetam and brivaracetam.

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Continue —> Brivaracetam: a novel antiepileptic drug for focal-onset seizuresTherapeutic Advances in Neurological Disorders – Linda J. Stephen, Martin J. Brodie, 2017