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Armel Stockis - One of the best experts on this subject based on the ideXlab platform.
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A review of the drug-drug interactions of the antiepileptic drug Brivaracetam.
Epilepsy research, 2020Co-Authors: Brian D. Moseley, Hugues Chanteux, Jean-marie Nicolas, Cédric Laloyaux, Barry E. Gidal, Armel StockisAbstract:Abstract Brivaracetam is an antiepileptic drug (AED) indicated for the treatment of focal seizures, with improved safety and tolerability vs first-generation AEDs. Brivaracetam binds with high affinity to synaptic vesicle protein 2A in the brain, which confers its antiseizure activity. Brivaracetam is rapidly absorbed and extensively biotransformed, and exhibits linear and dose-proportional pharmacokinetics at therapeutic doses. Brivaracetam does not interact with most metabolizing enzymes and drug transporters, and therefore does not interfere with drugs that use these metabolic routes. The favorable pharmacokinetic profile of Brivaracetam and lack of clinically relevant drug−drug interactions with commonly prescribed AEDs or oral contraceptives allows administration without dose adjustment, and avoids potential untoward events from decreased efficacy of an AED or oral contraceptive due to a drug−drug interaction. Few agents have been reported to affect the pharmacokinetics of Brivaracetam. The strong enzyme-inducing AEDs carbamazepine, phenytoin and phenobarbital/primidone have been shown to moderately lower Brivaracetam plasma concentrations, with no adjustment of Brivaracetam dose needed. Dose adjustment should be considered when Brivaracetam is coadministered with the more potent CYP inducer, rifampin. Additionally, caution should be used when adding or ending treatment with the strong enzyme inducer, St. John’s wort. In summary, Brivaracetam (50–200 mg/day) has a favorable pharmacokinetic profile and is associated with few clinically relevant drug–drug interactions.
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Safety and Tolerability of Adjunctive Brivaracetam in Pediatric Patients
Pediatric Drugs, 2019Co-Authors: Edwin Liu, Armel Stockis, Deanne Dilley, Belinda Mcdonough, Tony DanielsAbstract:Objective This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of Brivaracetam oral solution in children aged 1 month to
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Safety and Tolerability of Adjunctive Brivaracetam in Pediatric Patients < 16 Years with Epilepsy: An Open-Label Trial.
Paediatric drugs, 2019Co-Authors: Edwin Liu, Armel Stockis, Deanne Dilley, Belinda Mcdonough, Tony DanielsAbstract:This trial evaluated the short-term safety and tolerability, steady-state pharmacokinetics, and preliminary efficacy of Brivaracetam oral solution in children aged 1 month to
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extrapolation of a Brivaracetam exposure response model from adults to children with focal seizures
Clinical Pharmacokinectics, 2018Co-Authors: Rik C. Schoemaker, Janet R. Wade, Armel StockisAbstract:Introduction Prediction of Brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for Brivaracetam to children, using an existing population PK model for Brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration–effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A).
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Extrapolation of a Brivaracetam Exposure–Response Model from Adults to Children with Focal Seizures
Clinical Pharmacokinetics, 2018Co-Authors: Rik Schoemaker, Janet R. Wade, Armel StockisAbstract:Introduction Prediction of Brivaracetam effects in children was obtained by scaling an existing adult pharmacokinetic/pharmacodynamic (PK/PD) model for Brivaracetam to children, using an existing population PK model for Brivaracetam in children. The scaling was supported by estimating the change from adults to children in the concentration–effect relationship parameters for levetiracetam, a compound interacting with the same target protein (synaptic vesicle protein SV2A). Methods The existing adult PK/PD model for Brivaracetam was applied to a combined adult–pediatric dataset of levetiracetam. This model was then used to predict the effective oral twice-daily dose of Brivaracetam in children aged ≥4 to
Christian Wolff - One of the best experts on this subject based on the ideXlab platform.
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pharmacological profile of the novel antiepileptic drug candidate padsevonil interactions with synaptic vesicle 2 proteins and the gabaa receptor
Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Martyn Wood, Veronique Daniels, Laurent Provins, Christian Wolff, Rafal M Kaminski, Michel GillardAbstract:Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABAA receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil9s affinity for SV2A was higher than that of levetiracetam and Brivaracetam (pKi 8.5, 5.2 and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil9s interaction with SV2A differed from that of levetiracetam and Brivaracetam; it exhibited slower binding kinetics – dissociation t½ 30 min from the human protein at 37°C, compared with SIGNIFICANCE STATEMENT Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both pre- and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile – padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B and C) and micromolar affinity for the benzodiazepine binding site on GABAA receptors. Furthermore, padsevonil showed higher affinity for, and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam and Brivaracetam.
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Brivaracetam differentially affects voltage gated sodium currents without impairing sustained repetitive firing in neurons
CNS Neuroscience & Therapeutics, 2015Co-Authors: Isabelle Niespodziany, Véronique M. André, Nathalie Leclère, Etienne Hanon, Philippe Ghisdal, Christian WolffAbstract:Summary Aims Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Methods Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Results Brivaracetam and CBZ reduced INa in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.
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Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons
CNS neuroscience & therapeutics, 2014Co-Authors: Isabelle Niespodziany, Véronique M. André, Nathalie Leclère, Etienne Hanon, Philippe Ghisdal, Christian WolffAbstract:Summary Aims Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Methods Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Results Brivaracetam and CBZ reduced INa in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.
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Neurons; Voltage-gated sodium channel. Correspondence
2014Co-Authors: Christian Wolff, Etienne Hanon, Isabelle NiespodzianyAbstract:Aims: Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacol-ogy of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sus-tained repetitive firing (SRF). Methods: Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 lM) experiments were performed in comparison with 100 lM carbamazepine (CBZ). Results: Brivaracetam and CBZ reduced INa in N1E-115 cells (30 % and 40%, respectively) and primary cortical neurons (21 % and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions: The lack of effect of BRV on SRF in neu-rons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties
Eugen Trinka - One of the best experts on this subject based on the ideXlab platform.
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A systematic review and indirect treatment comparison of perampanel versus Brivaracetam as adjunctive therapy in patients with focal-onset seizures with or without secondary generalization.
Epilepsy research, 2020Co-Authors: Eugen Trinka, Wan Tsong, Sydney Toupin, Anna Patten, Katy Wilson, Jaana Isojarvi, Daniel JamesAbstract:Abstract Purpose To date, there has not been a single randomized controlled trial (RCT) conducted to directly compare the efficacy and safety of perampanel to Brivaracetam in the adjunctive treatment of focal-onset seizures. This study makes these comparisons through the use of indirect treatment comparison (ITC) methods. Methods A systematic review was conducted to identify RCTs that evaluated either one of perampanel or Brivaracetam in the treatment of patients with focal-onset seizures. The Bucher ITC method was then used to compare efficacy and safety outcomes between perampanel and Brivaracetam. Additional subgroup analyses, by levetiracetam usage (prior or concomitant), were conducted. Results Eight RCTs (four comparing perampanel to placebo, four comparing Brivaracetam to placebo) were included in the ITC. For patients taking concomitant levetiracetam, perampanel showed a significantly better responder rate compared to Brivaracetam [relative risk (RR) and 95 % confidence interval (CI): 2.62 (1.15, 5.99)]. For patients who had previously, or never, taken levetiracetam, there was no difference in the responder rate. In the overall population, both perampanel and Brivaracetam were more effective than placebo in terms of responder rate, seizure freedom, and secondarily generalized tonic-clonic seizure responder rate; however, for these outcomes, no evidence of a difference between perampanel and Brivaracetam was found. Patients taking Brivaracetam showed significantly less dizziness compared to patients taking perampanel. No differences for any other safety outcome were found. Conclusion Perampanel and Brivaracetam are effective for the adjunctive treatment of focal-onset seizures and display similar adverse event profiles. Perampanel demonstrated an improved focal-onset seizure responder rate compared to Brivaracetam in patients taking concomitant levetiracetam. This may be due to the similarity in the mechanism of action between Brivaracetam and levetiracetam.
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Intravenous Brivaracetam in the Treatment of Status Epilepticus: A Systematic Review
CNS Drugs, 2019Co-Authors: Francesco Brigo, Simona Lattanzi, Raffaele Nardone, Eugen TrinkaAbstract:Background Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. These properties make Brivaracetam potentially an ideal compound in the emergency setting. Objective The objective of our study was to review the evidence about the clinical efficacy and tolerability of intravenous Brivaracetam in the treatment of status epilepticus. Methods We systematically searched MEDLINE, EMBASE, Google Scholar, ClinicalTrials.gov, and conference proceedings to identify studies evaluating intravenous Brivaracetam as treatment for status epilepticus of any type in patients of any age. Searches were conducted on 3 December, 2018. Results Seven studies were included (37 patients; aged 22–85 years; 21 were female). The type and etiology of status epilepticus varied across studies. The number of drugs used prior to Brivaracetam to treat status epilepticus ranged from 1 to 8. The time from status epilepticus onset to Brivaracetam administration ranged from 0.5 h to 105 days. The initial Brivaracetam dose ranged from 50 to 400 mg. In case series, the proportion of patients achieving clinical status epilepticus cessation when Brivaracetam was administered as the last drug varied from 27 to 50%; in case reports, all patients had status epilepticus cessation. The time from Brivaracetam administration to status epilepticus cessation ranged from 15 min to 94 h. No serious adverse effects were reported. Conclusions The available data suggested that Brivaracetam can be a safe treatment option in patients with status epilepticus. The current evidence is however hampered by several confounding factors, and controlled studies are warranted to define the actual benefit of Brivaracetam for the treatment of status epilepticus.
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Intravenous Brivaracetam in the Treatment of Status Epilepticus: A Systematic Review
CNS drugs, 2019Co-Authors: Francesco Brigo, Simona Lattanzi, Raffaele Nardone, Eugen TrinkaAbstract:Brivaracetam is a high-affinity synaptic vesicle glycoprotein 2A ligand with high brain permeability and rapid onset of action. These properties make Brivaracetam potentially an ideal compound in the emergency setting. The objective of our study was to review the evidence about the clinical efficacy and tolerability of intravenous Brivaracetam in the treatment of status epilepticus. We systematically searched MEDLINE, EMBASE, Google Scholar, ClinicalTrials.gov, and conference proceedings to identify studies evaluating intravenous Brivaracetam as treatment for status epilepticus of any type in patients of any age. Searches were conducted on 3 December, 2018. Seven studies were included (37 patients; aged 22–85 years; 21 were female). The type and etiology of status epilepticus varied across studies. The number of drugs used prior to Brivaracetam to treat status epilepticus ranged from 1 to 8. The time from status epilepticus onset to Brivaracetam administration ranged from 0.5 h to 105 days. The initial Brivaracetam dose ranged from 50 to 400 mg. In case series, the proportion of patients achieving clinical status epilepticus cessation when Brivaracetam was administered as the last drug varied from 27 to 50%; in case reports, all patients had status epilepticus cessation. The time from Brivaracetam administration to status epilepticus cessation ranged from 15 min to 94 h. No serious adverse effects were reported. The available data suggested that Brivaracetam can be a safe treatment option in patients with status epilepticus. The current evidence is however hampered by several confounding factors, and controlled studies are warranted to define the actual benefit of Brivaracetam for the treatment of status epilepticus.
Isabelle Niespodziany - One of the best experts on this subject based on the ideXlab platform.
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Brivaracetam differentially affects voltage gated sodium currents without impairing sustained repetitive firing in neurons
CNS Neuroscience & Therapeutics, 2015Co-Authors: Isabelle Niespodziany, Véronique M. André, Nathalie Leclère, Etienne Hanon, Philippe Ghisdal, Christian WolffAbstract:Summary Aims Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Methods Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Results Brivaracetam and CBZ reduced INa in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.
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Brivaracetam Differentially Affects Voltage‐Gated Sodium Currents Without Impairing Sustained Repetitive Firing in Neurons
CNS neuroscience & therapeutics, 2014Co-Authors: Isabelle Niespodziany, Véronique M. André, Nathalie Leclère, Etienne Hanon, Philippe Ghisdal, Christian WolffAbstract:Summary Aims Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Methods Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Results Brivaracetam and CBZ reduced INa in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions The lack of effect of BRV on SRF in neurons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties.
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Neurons; Voltage-gated sodium channel. Correspondence
2014Co-Authors: Christian Wolff, Etienne Hanon, Isabelle NiespodzianyAbstract:Aims: Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacol-ogy of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sus-tained repetitive firing (SRF). Methods: Brivaracetam investigations on the voltage-gated sodium current (INa) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100–300 lM) experiments were performed in comparison with 100 lM carbamazepine (CBZ). Results: Brivaracetam and CBZ reduced INa in N1E-115 cells (30 % and 40%, respectively) and primary cortical neurons (21 % and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect INa in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75–93%. Conclusions: The lack of effect of BRV on SRF in neu-rons suggests that the reported inhibition of BRV on VGSC currents does not contribute to its antiepileptic properties
Michel Gillard - One of the best experts on this subject based on the ideXlab platform.
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pharmacological profile of the novel antiepileptic drug candidate padsevonil interactions with synaptic vesicle 2 proteins and the gabaa receptor
Journal of Pharmacology and Experimental Therapeutics, 2020Co-Authors: Martyn Wood, Veronique Daniels, Laurent Provins, Christian Wolff, Rafal M Kaminski, Michel GillardAbstract:Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABAA receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil9s affinity for SV2A was higher than that of levetiracetam and Brivaracetam (pKi 8.5, 5.2 and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil9s interaction with SV2A differed from that of levetiracetam and Brivaracetam; it exhibited slower binding kinetics – dissociation t½ 30 min from the human protein at 37°C, compared with SIGNIFICANCE STATEMENT Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both pre- and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile – padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B and C) and micromolar affinity for the benzodiazepine binding site on GABAA receptors. Furthermore, padsevonil showed higher affinity for, and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam and Brivaracetam.
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Binding characteristics of Brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: Relationship to anti-convulsant properties
European Journal of Pharmacology, 2011Co-Authors: Michel Gillard, Bruno Fuks, Karine Leclercq, Alain MatagneAbstract:Brivaracetam is a novel synaptic vesicle protein 2A (SV2A) ligand reported to be 10 fold more potent than levetiracetam in animal models of epilepsy. This study reports the binding profile of Brivaracetam in the brain of several species in relation to its anticonvulsant properties. The affinity, kinetics and selectivity of Brivaracetam and its tritiated form [(3)H]ucb 34714 have been determined by in vitro binding experiments in rat, human and mouse brain and on recombinant human SV2A. Brivaracetam and levetiracetam ex vivo binding to SV2A and anticonvulsant activities in audiogenic mice were compared in relation to dose and time. Brivaracetam bound selectively with 20 fold higher affinity than levetiracetam to SV2A. [(3)H]ucb 34714 bound reversibly and with high affinity to an homogenous population of binding sites in rat and human brain and to human SV2A expressed in CHO cells. The binding sites labeled by [(3)H]ucb 34714 in brain had the pharmacological characteristics of SV2A and no specific binding could be detected in the brain of SV2A(-/-) knock-out mice. The time- and dose-dependency of Brivaracetam and levetiracetam for binding to brain SV2A and for providing seizure protection in audiogenic mice correlated well; Brivaracetam being more potent and faster than levetiracetam. Brivaracetam is a potent and selective SV2A ligand. From its affinity and pharmacokinetics, simulations predicted that at therapeutically relevant doses, Brivaracetam should occupy more than 80% of SV2A in human brain, in line with levels of occupancy observed in pre-clinical models of epilepsy.