Brivaracetam

Rosenstiel, Philipp von; Perucca, Emilio

doi:10.1002/9781444316667.ch35

Cited by 11 publications

(8 citation statements)

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“…In study N01114, although BRV 50 and 150 mg/day showed a numerically greater reduction than PBO in baseline‐adjusted partial‐onset seizure frequency, the study failed to show statistically significant differences between BRV 50 or 150 mg/day and PBO in the primary efficacy analysis (van Paesschen et al., ). In these studies, the incidence of the most common adverse events (AEs) (headache, somnolence, fatigue, nausea, nasopharyngitis, and dizziness) and the proportion of patients discontinuing due to AEs were similar for BRV and PBO (Brodsky et al., ; von Rosenstiel & Perucca, ).…”

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confidence: 97%

Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double‐blind, placebo‐controlled trial

et al. 2013

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SUMMARYPurpose : Brivaracetam (BRV) is a novel high-affinity synaptic vesicle protein 2A ligand currently being investigated for the treatment of epilepsy. The purpose of this phase III study was to evaluate the efficacy and safety/tolerability of adjunctive BRV in adults with uncontrolled partial-onset (focal) seizures. Methods: This was a prospective, multicenter, randomized, double-blind, placebocontrolled, parallel-group, fixed-dose trial (N01253; NCT00464269). Adults aged 16-70 years with well-characterized partial epilepsy not fully controlled despite treatment with one or two antiepileptic drugs (AEDs) were enrolled. Patients who experienced eight or more partial-onset seizures, whether or not secondarily generalized, during the 8-week prospective baseline period were randomized (1:1:1:1) to receive twice-daily placebo (PBO) or BRV (5, 20, or 50 mg/day) without titration. The primary efficacy endpoint was percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/week during the 12-week treatment period. Comparison of BRV with PBO was sequential (50, 20 mg/day, then 5 mg/day). Secondary endpoints included ≥50% responder rate and median percent reduction from baseline in partialonset seizure frequency/week. Post hoc analyses included the primary efficacy endpoint evaluated over 28 days and exploratory subanalyses of efficacy by seizure subtype. Safety and tolerability assessments included treatment-emergent adverse events (TEAEs), laboratory tests, electrocardiography, vital signs, and physical and neurologic examinations. Key Findings: Of 400 patients randomized, 396 were included in the intent-to-treat (ITT) population (PBO n = 98, BRV 5 mg/day n = 97, BRV 20 mg/day n = 100, BRV 50 mg/day n = 101) and 392 comprised the modified ITT (mITT) population. A total of 361 (91.2%) of 396 patients completed the study. Most patients (78.3%) were receiving two concomitant AEDs. Percent reduction in partial-onset seizure frequency/week over PBO was À0.9% (p = 0.885) for BRV 5 mg/day, 4.1% (p = 0.492) for BRV 20 mg/ day, and 12.8% (p = 0.025) for BRV 50 mg/day (mITT population). Statistical significance was also achieved for the percent reduction over PBO in baseline-adjusted partial-onset seizure frequency/28 days for BRV 50 mg/day (22.0%; p = 0.004) but not for the other BRV dose groups. In the BRV 50 mg/day group, statistical significance was also seen for the ≥50% responder rate (BRV 32.7% vs. PBO 16.7%; p = 0.008) and median percent reduction from baseline in partial-onset seizure frequency/week (BRV 30.5% vs. PBO 17.8%; p = 0.003). In the exploratory subanalysis by seizure subtype, median percent reduction from baseline in seizure frequency/week and ≥50% responder rate were numerically greater than PBO in the BRV 20 and 50 mg/day groups for simple partial, complex partial, and secondarily generalized seizures. BRV was generally well tolerated, with the majority of TEAEs being mild-to-moderate in intensity. Of the TEAEs reported by ≥5% patients, those with a frequency >3% higher than PBO for...

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Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double‐blind, placebo‐controlled trial

et al. 2013

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“…BRV is extensively metabolized (>90%), primarily via hydrolysis of the acetamide group, and secondarily through hydroxylation mediated by cytochrome P450 (CYP) 2C19 (Bialer et al., 2010; Nicolas et al., 2012). The three major metabolites (hydroxy, acid, and hydroxyacid) are pharmacologically inactive (Sargentini‐Maier et al., 2008; von Rosenstiel & Perucca, 2009). BRV is eliminated as urinary metabolites with >95% of a radioactive dose recovered in the urine within 72 h, including only 8.6% as unchanged BRV (Sargentini‐Maier et al., 2008).…”

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Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb, randomized, controlled trial

et al. 2012

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SUMMARYPurpose: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV), a novel high-affinity synaptic vesicle protein 2A ligand that also displays inhibitory activity at neuronal voltage-dependent sodium channels, in adult epilepsy patients with uncontrolled partial-onset seizures. Methods: A phase IIb, double-blind, randomized, placebocontrolled, parallel-group, dose-ranging study (N01114; NCT00175929) was conducted in patients aged 16-65 years. To be included in the study, patients were required to have experienced four or more partial-onset seizures during a 4-week prospective baseline, despite treatment with 1-2 concomitant antiepileptic drugs. Patients were randomized in a ratio of 1:1:1 to receive BRV 50 mg/day (BRV50), 150 mg/day (BRV150), or placebo. A 3-week uptitration period was followed by a 7-week maintenance period (total treatment period of 10 weeks). Key Findings: A total of 157 patients were randomized (intent-to-treat [ITT] population; BRV50 n = 53, BRV150 n = 52, placebo n = 52) and overall 148 (94.3%) completed the study. The percent reduction in baseline-adjusted partial-onset seizure frequency/week over placebo during the 7-week maintenance period (primary efficacy outcome) did not reach statistical significance (14.7% for BRV50 [p = 0.093] and 13.6% for BRV150 [p = 0.124]). However, during the entire 10-week treatment period a statistically significant difference was observed for both BRV groups (17.7% for BRV50 [p = 0.026] and 16.3% for BRV150 [p = 0.043]). The median percent reduction from baseline in partial-onset seizure frequency/week during the maintenance period was 38.2% for BRV50 (p = 0.017) and 30.0% for BRV150 (p = 0.113) versus 18.9% in the placebo group. During the treatment period, this was 34.9% for BRV50 (p = 0.004) and 28.3% for BRV150 (p = 0.070) compared with 16.3% for placebo. Fifty percent responder rates during the maintenance period were 23.1% for placebo compared with 39.6% for BRV50 (odds ratio [OR] 2.17, p = 0.077) and 33.3% for BRV150 (OR 1.66, p = 0.261). During the treatment period, 50% responder rates were 17.3% for placebo compared with 35.8% for BRV50 (OR 2.69, p = 0.038) and 30.8% for BRV150 (OR 2.15, p = 0.114). Nine patients were free from partial-onset seizures during the 10-week treatment period (five patients [9.4%] in the BRV50 group and three [5.8%] in the BRV150 group compared with one patient [1.9%] in the placebo group). Treatment-emergent adverse events (TEAEs) reported during the treatment period were mostly mild-to-moderate with similar incidence across treatment groups (BRV50 36/53, 67.9%; BRV150 35/52, 67.3%; placebo 37/52, 71.2%). The most frequently reported TEAEs in BRV groups were headache, fatigue, nasopharyngitis, nausea, somnolence, and dizziness, although nausea had a higher incidence in the placebo group. Significance: In this double-blind, placebo-controlled, phase IIb study of adjunctive BRV (50 and 150 mg/day) in adults with uncontrolled partial-onset seizures, the primary efficacy analysis did not reach stat...

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“…In order to estimate a target value for SV2A binding in the brain, a simulation of BRV was first performed, using a dosing regimen of 25 mg b.i.d. This dose was previously identified as a clinically effective dose in patients with partial epilepsy [2,8]. Predicted brain concentration profiles from the physiologically based pharmacokinetic model were used in conjunction with the mouse ex vivo binding pharmacokinetic/pharmacodynamic model to derive SV2A binding versus time profiles (fig.…”

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confidence: 99%

“…Brivaracetam (BRV) is a novel, high‐affinity ligand of synaptic vesicle protein 2A (SV2A) that also displays weak inhibitory activity at neuronal voltage‐dependent sodium channels. It is currently in phase 3 of clinical development for epilepsy [2]. SV2A is involved in the presynaptic release of neurotransmitters, and data in transgenic mice indicate that even partial SV2A deficiency may lead to increased seizure vulnerability and accelerated epileptogenesis [3].…”

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Physiologically Based Pharmacokinetic/Pharmacodynamic Animal‐to‐Man Prediction of Therapeutic Dose in a Model of Epilepsy

Brochot

Zamacona

Stockis

2010

Basic Clin Pharma Tox

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Animal-to-man extrapolation and therapeutic dose prediction are illustrated with two molecules designed to treat epilepsy. Synaptic vesicle protein 2A (SV2A) is the primary molecular target for their anticonvulsive effect, but additional mechanisms may also contribute. Brivaracetam (BRV), currently in phase 3 of clinical development, was used as the benchmark compound. A pharmacokinetic ⁄ pharmacodynamic model was built in NONMEM, relating the brain tissue concentrations of BRV in mice and the proportion of animals protected against convulsions in the pharmacological model of audiogenic seizures. Brain concentrations were linked with ex vivo binding to predict brain SV2A occupancy. A physiologically based pharmacokinetic model was developed for predicting BRV concentrations in human plasma and brain tissue. Predicted plasma profiles were in good agreement with observations. Predicted human brain concentrations of BRV and the mouse ex vivo binding pharmacokinetic ⁄ pharmacodynamic model were used to extrapolate brain SV2A occupancy at the human therapeutic dose. Secondly, for another compound also exhibiting selective affinity for the same target, similar pharmacokinetic ⁄ pharmacodynamic models were built from audiogenic seizure mouse data. Various dosing regimens of the new compound were simulated in order to reach the same brain SV2A occupancy as for the reference compound. These estimations support early development. Assumptions and limitations of the approach are discussed.Epilepsy is one of the most common serious neurological disorders, with a prevalence close to 1% of the world's population. Epilepsy is not a single disease, but a variety of disorders reflecting underlying brain dysfunction that may result from many different causes. Despite appropriate drug treatment, epilepsy remains uncontrolled in more than a third of affected individuals. Combination therapy is the mainstay of treatment in these patients. Uncontrolled epilepsy is associated with increased mortality and physical injuries, and a range of psychosocial morbidities, posing a substantial economic burden on individuals and society. Limitations of the present anti-epilepsy drugs include suboptimal efficacy and their association with a host of adverse reactions. Continued efforts are being made in drug development to overcome these shortcomings employing a range of strategies, including modification of the structure of existing drugs, targeting novel molecular substrates and non-mechanism-based screening of compounds in traditional and newer animal models [1]. The ultimate goal is to develop novel agents that can prevent the occurrence of seizures and the progression of epilepsy in at-risk individuals.Brivaracetam (BRV) is a novel, high-affinity ligand of synaptic vesicle protein 2A (SV2A) that also displays weak inhibitory activity at neuronal voltage-dependent sodium channels. It is currently in phase 3 of clinical development for epilepsy [2]. SV2A is involved in the presynaptic release of neurotransmitters, and data in transgeni...

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Brivaracetam

Cited by 11 publications

References 12 publications

Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double‐blind, placebo‐controlled trial

Brivaracetam as adjunctive treatment for uncontrolled partial epilepsy in adults: A phase III randomized, double‐blind, placebo‐controlled trial

Efficacy and tolerability of adjunctive brivaracetam in adults with uncontrolled partial‐onset seizures: A phase IIb, randomized, controlled trial

Physiologically Based Pharmacokinetic/Pharmacodynamic Animal‐to‐Man Prediction of Therapeutic Dose in a Model of Epilepsy

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