Influence of dose and antiepileptic comedication on brivaracetam serum concentrations in patients with epilepsy

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, −49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.     

Comparison of the effectiveness and tolerability of perampanel and brivaracetam: a real‐world,observational, retrospective study

Aim. Perampanel (PER) and brivaracetam (BRV) are third‐generation antiseizure medications. The aim of the present retrospective, double‐centre study was to compare the effectiveness and tolerability between PER and BRV in adult patients with epilepsy. Methods. We reviewed the clinical charts of patients affected by epilepsy, admitted to the Epilepsy Centre at the University Hospital of Rome “Tor Vergata” and the Cardarelli Hospital in Naples, who started BRV or PER as add‐on treatment for controlling seizures with a follow‐up of 12 months. Seizure freedom, >50% seizure reduction, retention rate, and adverse events reported during follow‐up were compared between the two drugs. Moreover, we considered the effects of both drugs in specific subsets of patients: age ≥60 years, male or female, in patients with genetic generalized epilepsy, and considering previous treatment with levetiracetam (LEV). Results. Forty‐three patients treated with BRV and 64 patients treated with PER were included in this study and followed at both sites for 12 months. Similar effectiveness was observed between BRV and PER, with similar rates of seizure freedom (30% vs 31%) and >50% seizure reduction (32% vs 34%) during follow‐up. Moreover, PER and BRV discontinuation rates, due to ineffectiveness or adverse events, were similar. Groups of patients who started BRV or PER as first add‐on treatments were also compared but no differences in effectiveness or tolerability were identified. Lastly, BRV was shown to be more effective in patients who were not previously treated with LEV. Conclusions. This retrospective study reveals comparable effectiveness and tolerability between PER and BRV also when used as first add‐on treatments, in patients with epilepsy.     

布瓦西坦致儿童不良反应的文献分析

目的 分析布瓦西坦致儿童不良反应(ADR)的一般规律及特点,为临床安全用药提供参考。方法 以"布瓦西坦" "布立西坦" "不良反应"和"副作用"等为中文检索词,以"Brivaracetam" "adverse reaction" "adverseeffects"ADR "和" side effect"等为英文检索词,对中国学术期刊全文数据库(CNKI)、万方数据库(Wanfang Data)、维普生物医学数据库(VIP)、PubMed、Web of Sciene和Embase等数据库进行文献检索,检索时限均为数据库建库起至2024年1月31日。对纳入研究患者性别、年龄、用药情况、联合用药、ADR临床表现等进行统计分析。结果 共纳入文献13篇,纳入病例849例,其中男性458例(53.9 %)、女性391例(46.1 %),ADR共累及6个系统/器官,以神经系统(39.22 %)和精神疾病(31.86 %)为主,包括嗜睡、癫痫发作恶化、抽搐、易怒、攻击性、精神运动机能亢进、行为问题等。大多数ADR是可逆且预后良好的,但仍有部分患者在进行干预治疗后产生了不良结局,甚至死亡。结论 布瓦西坦可致儿童严重ADR的发生,临床应关注该药的合理使用,加强用药监护和随访,以确保患者临床用药安全。     

Brivaracetam: a rational drug discovery success story

Levetiracetam, the alpha-ethyl analogue of the nootropic piracetam, is a widely used antiepileptic drug (AED) that provides protection against partial seizures and is also effective in the treatment of primary generalized seizure syndromes including juvenile myoclonic epilepsy. Levetiracetam was discovered in 1992 through screening in audiogenic seizure susceptible mice and, 3 years later, was reported to exhibit saturable, stereospecific binding in brain to a approximately 90 kDa protein, later identified as the ubiquitous synaptic vesicle glycoprotein SV2A. A large-scale screening effort to optimize binding affinity identified the 4-n-propyl analogue, brivaracetam, as having greater potency and a broadened spectrum of activity in animal seizure models. Recent phase II clinical trials demonstrating that brivaracetam is efficacious and well tolerated in the treatment of partial onset seizures have validated the strategy of the discovery programme. Brivaracetam is among the first clinically effective AEDs to be discovered by optimization of pharmacodynamic activity at a molecular target.     

Anti-convulsive and anti-epileptic properties of brivaracetam (ucb 34714), a high-affinity ligand for the synaptic vesicle protein, SV2A

BACKGROUND AND PURPOSE: Screening of 12,000 compounds for binding affinity to the synaptic vesicle protein 2A (SV2A), identified a high-affinity pyrrolidone derivative, brivaracetam (ucb 34714). This study examined its pharmacological profile in various in vitro and in vivo models of seizures and epilepsy, to evaluate its potential as a new antiepileptic drug. EXPERIMENTAL APPROACH: The effects of brivaracetam and levetiracetam on epileptiform activity and seizure expression were examined in rat hippocampal slices, corneally kindled mice, audiogenic seizure-susceptible mice, maximal electroshock and pentylenetetrazol seizures in mice, hippocampal-kindled rats, amygdala-kindled rats and genetic absence epilepsy rats. KEY RESULTS: Brivaracetam and levetiracetam reduced epileptiform responses in rat hippocampal slices, brivaracetam being most potent. Brivaracetam also differed from levetiracetam by its ability to protect against seizures in normal mice induced by a maximal electroshock or maximal dose of pentylenetetrazol. In corneally kindled mice and hippocampal-kindled rats, brivaracetam induced potent protection against secondarily generalized motor seizures and showed anti-kindling properties superior to levetiracetam. In amygdala-kindled rats, brivaracetam induced a significant suppression in motor-seizure severity and, contrary to levetiracetam, reduced the after-discharge at a higher dose. Audiogenic seizure-susceptible mice were protected more potently against the expression of clonic convulsions by brivaracetam than by levetiracetam. Brivaracetam induced a more complete suppression of spontaneous spike-and-wave discharges in genetic absence epilepsy rats than levetiracetam. CONCLUSIONS AND IMPLICATIONS: Brivaracetam has higher potency and efficacy than levetiracetam as an anti-seizure and anti-epileptogenic agent in various experimental models of epilepsy, and a wide therapeutic index.     

The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after single increasing oral doses in healthy males

AIMS: The objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses. METHODS: Healthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10-1400 mg) and one dose of placebo during three periods of a randomized, double-blind, placebo-controlled study. The effect of food on its pharmacokinetics was assessed using a standard two-way crossover design in a further eight subjects who received two single oral doses of brivaracetam (150 mg) in the fasting state and after a high fat meal. RESULTS: Adverse events, none of which were serious, were mostly CNS-related and included somnolence, dizziness, and decreased attention, alertness, and motor control. Their incidence, severity and duration were dose-related. The maximum tolerated dose was established to be 1000 mg. Severe somnolence lasting 1 day occurred in one subject following 1400 mg. Brivaracetam was rapidly absorbed under fasting conditions, with a median t(max) of approximately 1 h. C(max) was dose-proportional from 10 to 1400 mg, whereas AUC deviated from dose linearity above 600 mg. A high-fat meal had no effect on AUC (point estimate 0.99, 90%CI: 0.92-1.07) but delayed t(max) (3 h) and decreased C(max) (point estimate 0.72, 90%CI: 0.66-0.79). CONCLUSIONS: Brivaracetam was well tolerated after increasing single doses that represent up to several times the expected therapeutic dose. Brivaracetam was found to have desirable pharmacokinetic properties. The most common adverse events were somnolence and dizziness.     

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy

Objective

This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add-On First Italian Network Study (BRIVAFIRST).

Methods

BRIVAFIRST was a 12-month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5–20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6.

Results

A total of 994 participants were included. During the 1-year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5–20, and >20 seizures per month (p < .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p < .001). SSR was reached by 51.2% and 26.5% participants with a history of 1–5 and ≥6 ASMs (p < .001); the corresponding rates of SSF were 24.7% and 4.5% (p < .001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p < .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1–5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs.

Significance

The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.