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.

Keywords: brivaracetam; efficacy; epilepsy; focal seizures; pharmacokinetics; tolerability.

Figure 1

Ex vivo binding of brivaracetam and levetiracetam in rat and human cerebral cortex. Notes: Republished with permission of Elsevier Science and Technology Journals, from Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties, Gillard M, Fuks B, Leclercq K, Matagne A, Volume 664, Edition (1–3), 2011; permission conveyed through Copyright Clearance Center, Inc.

Figure 2

Differential interaction of BRV and LEV with SV2A. Notes: Combination experiments assessing the impact of the allosteric SV2A modulator UCB 1244283 on [³H]BRV and [³H]LEV binding in recombinant cells expressing SV2A. A major increase in affinity (K_d) for SV2A was seen for [³H]BRV, and maximum binding capacity (B_max) increased for [³H]LEV, suggesting that BRV and LEV have differential interactions with SV2A. Republished with permission of John Wiley and Sons Inc, from Brivaracetam: rationale for discovery and preclinical profile of a selective SV2A ligand for epilepsy treatment, Klitgaard H, Matagne A, Nicolas JM, et al, Volume 57, Edition 4, 2016; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: BRV, brivaracetam; LEV, levetiracetam.

Figure 3

Displacement of the SV2A PET tracer [¹¹C]UCB-J after injection of 5 mg/kg BRV or 30 mg/kg LEV (administered intravenously 45 minutes after the PET tracer). Notes: The displacement graph shows the amount of radioactivity in the brain over time. The baseline curve (black squares) shows that the tracer by itself leaves the brain very slowly (gradual reduction in radioactivity over time). When BRV or LEV is administered, radioactivity in the brain is quickly reduced (dark blue circles and light blue triangles, respectively). This is because BRV and LEV displace the tracer. The BRV curve is steeper than the LEV curve, which means that BRV displaces the tracer more quickly than LEV does; therefore, it enters the brain more quickly than LEV. The steepness of these curves was used to estimate the speed of entry of LEV and BRV. Republished with permission of John Wiley and Sons Inc, from Brivaracetam, a selective high-affinity synaptic vesicle protein 2A (SV2A) ligand with preclinical evidence of high brain permeability and fast onset of action, Nicolas JM, Hannestad J, Holden D, et al, Volume 57, Edition 2, 2016; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: BRV, brivaracetam; LEV, levetiracetam; PET, positron-emission tomography; SUV, standardized uptake value; TAC, time–activity curve.

Figure 4

Categorized percentage reduction in focal seizure frequency per 28 days in the pooled Phase III population. Adapted from Ben-Menachem E, Mameniškienė R, Quarato PP, et al. Efficacy and safety of brivaracetam for partial-onset seizures in three pooled clinical studies. Neurology. 2016;87(3):314–323. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer. Please contact healthpermissions@wolterskluwer.com for further information. Abbreviation: BRV, brivaracetam.

Figure 5

Percentage reduction from baseline in focal seizure frequency by number of prior AEDs in the pooled Phase III population. Reproduced from Ben-Menachem E, Mameniškienė R, Quarato PP, et al. Efficacy and safety of brivaracetam for partial-onset seizures in three pooled clinical studies. Neurology. 2016;87(3):314–323. Promotional and commercial use of the material in print, digital or mobile device format is prohibited without the permission from the publisher Wolters Kluwer. Please contact healthpermissions@wolterskluwer.com for further information. Abbreviations: AED, antiepileptic drug; BRV, brivaracetam.

Figure 6

Responder rates (≥50% and ≥75%) and complete freedom from SGTCS in the pooled Phase III population. Adapted from Elsevier Science and Technology Journals, Efficacy, safety, and tolerability of adjunctive brivaracetam for secondarily generalized tonic-clonic seizures: pooled results from three phase III studies, Moseley BD, Sperling MR, Asadi-Pooya AA, et al, Volume 127, 2016; permission conveyed through Copyright Clearance Center, Inc. Abbreviations: BRV, brivaracetam; SGTCS, secondarily generalized tonic–clonic seizure.

Figure 7

Kaplan–Meier plot of time to onset of sustained ≥50% responder status in the pooled Phase III population. Notes: For each day, P versus placebo was ≤0.003 for BRV 50 mg/day and <0.001 for BRV 100 mg/day and 200 mg/day. Reproduced from John Wiley and Sons Inc, Time to onset of sustained ≥50% responder status in patients with focal (partial-onset) seizures in three phase III studies of adjunctive brivaracetam treatment, Klein P, Johnson ME, Schiemann J, Whitesides J, Volume 58, 2017; permission conveyed through Copyright Clearance Center, Inc. Abbreviation: BRV, brivaracetam.

Figure 8

Seizure reduction and responder rates. (A) Median (IQR) percentage reduction in focal seizures from baseline; (B) ≥50% responder rates over time for BRV modal doses 50–200 mg/day in pooled long-term follow-up analysis. Notes: Adapted with permission of John Wiley and Sons Inc, from Safety, tolerability, and seizure control during long-term treatment with adjunctive brivaracetam for partial-onset seizures, Toledo M, Whitesides J, Schiemann J, et al, Volume 57, Edition 7, 2016; permission conveyed through Copyright Clearance Center, Inc. © 2016 The Authors. Epilepsia published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy. Abbreviations: BRV, brivaracetam; IQR, interquartile range.