Brivaracetam, a selective high‐affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action

Abstract

SUMMARYObjective: Rapid distribution to the brain is a prerequisite for antiepileptic drugs used for treatment of acute seizures. The preclinical studies described here investigated the high-affinity synaptic vesicle glycoprotein 2A (SV2A) antiepileptic drug brivaracetam (BRV) for its rate of brain penetration and its onset of action. BRV was compared with levetiracetam (LEV). Methods: In vitro permeation studies were performed using Caco-2 cells. Plasma and brain levels were measured over time after single oral dosing to audiogenic mice and were correlated with anticonvulsant activity. Tissue distribution was investigated after single dosing to rat (BRV and LEV) and dog (LEV only). Positron emission tomography (PET) displacement studies were performed in rhesus monkeys using the SV2A PET tracer [11 C]UCB-J. The time course of PET tracer displacement was measured following single intravenous (IV) dosing with LEV or BRV. Rodent distribution data and physiologically based pharmacokinetic (PBPK) modeling were used to compute blood-brain barrier permeability (permeability surface area product, PS) values and then predict brain kinetics in man. Results: In rodents, BRV consistently showed a faster entry into the brain than LEV; this correlated with a faster onset of action against seizures in audiogenic susceptible mice. The higher permeability of BRV was also demonstrated in human cells in vitro. PBPK modeling predicted that, following IV dosing to human subjects, BRV might distribute to the brain within a few minutes compared with approximately 1 h for LEV (PS of 0.315 and 0.015 ml/min/g for BRV and LEV, respectively). These data were supported by a nonhuman primate PET study showing faster SV2A occupancy by BRV compared with LEV. Significance: These preclinical data demonstrate that BRV has rapid brain entry and fast brain SV2A occupancy, consistent with the fast onset of action in the audiogenic seizure mice assay. The potential benefit of BRV for treatment of acute seizures remains to be confirmed in clinical studies.

Newer Antiepileptic Drugs in Status Epilepticus: Prescription Trends and Outcomes in Comparison with Traditional Agents

“…This may reflect a suboptimal SE treatment approach with insufficient doses of newer AEDs, or their prescriptions without or with underdosed benzodiazepines as first line treatment (34). However, in animal studies levetiracetam has shown a relatively slow penetration into the central nervous system, with latencies of more than 1 hour to achieve maximum concentrations in the cerebrospinal or in the brain extra-cerebral fluid (35)(36)(37). Animal studies with phenytoin, on the other side, shows maximum concentrations in cerebrospinal and brain extra-cerebral fluids within 9-13minutes and 39-34minutes, respectively (38).…”

A Validated Lc-MS/MS Method for Pharmacokinetic Study of Brivaracetam in Healthy Rabbits

“…[9][10][11][12][13]. As per literature review, no LC-MS/MS method was available for determination of brivaracetam alone from rabit plasma, the validated method was successfully applied for the determination of Tmax, Cmax, AUC0→t and AUC0→α using rabbits as test animals.…”

“…Brivaracetam chemically is a 4-npropyl analog of levetiracetam and a racetam derivative with anticonvulsant properties [7,8]. Literature survey pharmacokinetics and metabolism of 14C-brivaracetam, metabolism studies of brivaracetam and gemfibrozil, clinical trials of adjunctive brivaracetam for refractory partial-onset seizures, identification of drug metabolites in human plasma or serum integrating metabolite prediction, by LC-HRMS methods are reported for the drug [9][10][11][12][13]. To best of our knowledge, no published LC-MS/MS-based methods for the pharmacokinetic study of brivaracetam in healthy rabbits.…”

Overexpression of Synaptic Vesicle Protein 2A Inhibits Seizures and Amygdaloid Electroencephalogram Activity in Pilocarpine-induced Pharmacoresistant Epileptic Rats

“…LEV has only modest affinity for SV2A, but BRV is a selective, high-affinity SV2A ligand with promising antiepileptic properties and fast onset of action. BRV, which has rapid brain entry and fast brain SV2A occupancy [17], provides potent and complete seizure suppression in animal models of partial, generalized, and drug-resistant seizures [32].…”

“…Expression of SV2A is correlated with the clinical response to LEV and predicts LEV efficacy in patients with epilepsy secondary to tumor [15]. The novel LEV analogs, brivaracetam (BRV) and seletracetam, which are effective as an adjunctive treatment in epilepsy, also bind to SV2A [16,17].…”