A review of the pharmacology and clinical efficacy of brivaracetam

Abstract

Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30-fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10–1,000 mg) and multiple (200–800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50–200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic–clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug–drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV.

Effects of antiepileptic drugs on cortical excitability in humans: A TMS‐EMG and TMS‐EEG study

“…BRV had no effect on SICI. This is in accord with the literature where levetiracetam also did not alter SICI (Reis et al, ; Sohn et al, ; Solinas et al, ), and with the mode of action of BRV and levetiracetam without any modulating activity directly at the GABAA receptor (Klein et al, ; Lyseng‐Williamson, ).…”

“…This effect may be explained by its specific binding to the presynaptic vesicle protein SV2A. This protein is expressed on excitatory and inhibitory neurons throughout the central nervous system (Klein et al, ), but BRV may exert its antiepileptic effects predominantly through depression of excitatory neurotransmission (Yang et al, ).The current BRV findings are in agreement with previous TMS‐EMG studies that reported a depression of MEP input–output curves under levetiracetam (Reis et al, ; Sohn, Kaelin‐Lang, Jung, & Hallett, ).…”

“…Subjects participated in four experimental sessions in pseudo‐randomized order, balanced across subjects, and separated by at least 1 week to avoid carry‐over effects from the previous session. Study drugs were: (a) CBZ, a VGSC blocker (Macdonald, ), (b) BRV, a specific ligand to the presynaptic vesicle protein SV2A with high affinity and selectivity (Klein et al, ; Klitgaard et al, ), and (c) TGB, a selective GABA reuptake inhibitor (Suzdak & Jansen, ). The timeline of an experimental session is illustrated in Figure .…”

“…Here we extend previous findings by studying the effects of carbamazepine (CBZ), brivaracetam (BRV) and tiagabine (TGB) on cortical excitability and inhibition in healthy human subjects testing both TMS evoked electromyographic (EMG) and TMS‐EEG responses. Drugs were chosen because of their common use as antiepileptic drugs and well‐defined specific modes of action: CBZ is a VGSC blocker (Macdonald, ), BRV decreases neuronal excitability primarily through selective binding to the presynaptic vesicle protein SV2A (Klein, Diaz, Gasalla, & Whitesides, ; Klitgaard et al, ), and TGB is a selective GABA reuptake inhibitor (Suzdak & Jansen, ). Subjects received a single oral dose of CBZ, BRV, or TGB in a double‐blinded, randomized, placebo‐controlled crossover design.…”

A single‐center, open‐label positron emission tomography study to evaluate brivaracetam and levetiracetam synaptic vesicle glycoprotein 2A binding in healthy volunteers

“…More rapid penetration of BRV versus LEV provides the potential for more rapid onset of action and therefore could be important in acute unremitting seizures requiring prompt therapeutic intervention. A clinical study investigating the efficacy and safety of BRV as treatment for increased seizure activity in an epilepsy monitoring unit setting (EP0087; http://www.clinicaltrials.gov NCT03021018) has been completed and concluded that intravenous lorazepam, intravenous 100 mg brivaracetam, and intravenous 200 mg brivaracetam showed similar efficacy in acute seizures .…”