Posts Tagged brivaracetam

[ARTICLE] Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Full Text

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

 

Introduction

Since the introduction of bromides as the first effective antiepileptic drugs (AEDs),1 chronic AED treatment that consisted of the sustained prevention of epileptic seizures has remained the standard of epilepsy therapy.2 Before to the introduction of the newer generation of AEDs, a limited number of drugs were available that addressed the blockade of sodium channels, acting on gamma-aminobutyric acid (GABA) type A receptors, or interacting with calcium channels as the leading modes of action.3 With the introduction of the newer AEDs a heterogeneous group of drugs appeared, some of them offering new mechanisms of action2 including the blockade of GABA aminotransferase (vigabatrin [VGB]), GABA re-uptake from the synaptic cleft (tiagabine [TGB]), the modulation of calcium channels (gabapentin [GBP], pregabalin [PGB]), the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor antagonism (perampanel [PER]), and the binding to the presynaptic SV2A receptor site which is the unique mode of action of levetiracetam (LEV) and brivaracetam (BRV), the AEDs this review will cover. The authors will summarize the development of both compounds as derivatives of piracetam, review the currently available preclinical and clinical data, and discuss the question of whether BRV has the potential to be recognized as being superior to LEV and if it can replace it as the standard AED with the main mode of action both AEDs reflect.[…]

 

Continue —->  Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Bernhard J. Steinhoff, Anke M. Staack, 2019

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[ARTICLE] Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Full Text

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Since the introduction of bromides as the first effective antiepileptic drugs (AEDs),1 chronic AED treatment that consisted of the sustained prevention of epileptic seizures has remained the standard of epilepsy therapy.2 Before to the introduction of the newer generation of AEDs, a limited number of drugs were available that addressed the blockade of sodium channels, acting on gamma-aminobutyric acid (GABA) type A receptors, or interacting with calcium channels as the leading modes of action.3 With the introduction of the newer AEDs a heterogeneous group of drugs appeared, some of them offering new mechanisms of action2 including the blockade of GABA aminotransferase (vigabatrin [VGB]), GABA re-uptake from the synaptic cleft (tiagabine [TGB]), the modulation of calcium channels (gabapentin [GBP], pregabalin [PGB]), the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor antagonism (perampanel [PER]), and the binding to the presynaptic SV2A receptor site which is the unique mode of action of levetiracetam (LEV) and brivaracetam (BRV), the AEDs this review will cover. The authors will summarize the development of both compounds as derivatives of piracetam, review the currently available preclinical and clinical data, and discuss the question of whether BRV has the potential to be recognized as being superior to LEV and if it can replace it as the standard AED with the main mode of action both AEDs reflect.[…]

 

Continue —-> Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Bernhard J. Steinhoff, Anke M. Staack, 2019

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[Abstract] Brivaracetam in the treatment of patients with epilepsy – clinical experiences

Objectives. To assess first clinical experiences with Brivaracetam (BRV) in the treatment of epilepsies.
Methods. Data on patients treated with BRV from February to December 2016 and with at least one clinical follow-up were collected from electronic patient records. Data on safety and efficacy were evaluated retrospectively.
Results. In total, 93 patients were analysed; 12 (12.9%) received BRV in monotherapy. Mean duration of follow up was 4.85 months (MD=4 months; SD=3.63). Fifty-seven patients had more than one seizure per month at baseline and had a follow-up of more than 4 weeks; the rate of ≥50% responders was 35.1% (n=20) in this group, of which five (8.8%) patients were newly seizure free.
In 50.5% (47/93), patients were switched from Levetiracetam (LEV) to BRV, of which 43 (46.2%) were switched immediately. Adverse events (AE) occurred in 39.8%, with 22.6% being behavioural, and 25.8% non-behavioural. LEV-related AE (LEV-AE) were significantly reduced by switching to BRV.
The discontinuation of BRV was reported in 26/93 patients (28%); 10 of those were switched back to LEV with an observed reduction of AE in70%.
For clinical reasons, 12 patients received BRV in monotherapy, 75% were seizure free and previous LEV-AE improved in 6/9 patients. BRV-related AE occurred in 5/12 cases, five patients discontinued BRV.
Conclusion. BRV seems to be a safe, easy and effective option in the treatment of patients with epilepsy, especially in the treatment of patients that have psychiatric comorbidities and might not be good candidates for LEV-treatment. BRV broadens the therapeutic spectrum and facilitates personalized treatment.

 

via Frontiers | Brivaracetam in the treatment of patients with epilepsy – clinical experiences | Neurology

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

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.

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.35 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.

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

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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

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