Introduction

Both levetiracetam (LEV) and brivaracetam (BRV) eliminate the electroencephalogram photoparoxysmal response (PPR) in the human phase IIa photosensitivity model of epilepsy. The physiochemical properties of BRV differ from those of LEV, having higher potency and lipophilicity plus 10- to 15-fold greater affinity for synaptic vesicle glycoprotein 2A.

Objective

We compared the rapidity of the effects of both drugs in the central nervous system (CNS) of patients with photosensitive epilepsy using time to PPR elimination post-intravenous infusion as a pharmacodynamic endpoint.

Methods

Using a randomized, double-blind, two-period, balanced, crossover design, we tested patients with photosensitive epilepsy with equipotent milligram doses of intravenous LEV 1500 mg versus BRV 100 mg post-15-min intravenous infusion (part 1) and post-5-min intravenous infusion (part 2, same doses). Eight patients per part were deemed sufficient with 80% power to determine a 70% reduction for intravenous BRV:LEV intrapatient time ratio to PPR elimination, with a 0.05 two-sided significance level. Plasma antiseizure medicine concentrations were measured using liquid chromatography/mass spectrometry.

Results

Nine patients [six women; mean age 27.8 years (range 18–42)] completed the study; seven of these participated in both parts 1 and 2. In 31 of 32 instances, patients experienced PPR elimination. In mixed-effects model time analysis, BRV eliminated PPRs more quickly than did LEV (median 2 vs. 7.5 min, respectively). However, no statistically significant difference in BRV:LEV time ratio to PPR elimination was observed for two of our multiple primary outcomes: for the 15-min infusion alone (p = 0.22) or the 5-min infusion alone (p = 0.11). However, BRV was faster when we excluded an outlier patient in part 1 (p = 0.0016). For our remaining primary outcome, parts 1 and 2 data combined, the median intrapatient BRV:LEV time ratio was 0.39 [95% confidence interval (CI) 0.16–0.91], i.e., PPR elimination was 61% faster with BRV, p = 0.039. PPR was completely eliminated in ≤ 2 min in 11 patients with BRV and in four patients with LEV. No period or carryover effects were seen. No serious or severe adverse effects occurred. At PPR elimination (n = 16), median plasma [BRV] was 250 ng/mL (range 30–4100) and median plasma [LEV] was 28.35 μg/mL (range 1–86.7).

Conclusion

Outcome studies directly comparing LEV and BRV are needed to define the clinical utility of the response with BRV, which was several minutes faster than that with LEV.

Clinical trials

ClinTrials.gov Identifier = NCT03580707; registered 07-09-18

中文翻译：

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中枢神经系统对布立西坦与左乙拉西坦的光阵发性反应的快速反应：在光敏性癫痫患者中进行的一项随机、双盲、交叉试验。

介绍

左乙拉西坦 (LEV) 和布立西坦 (BRV) 均可消除人类 IIa 期癫痫光敏模型中的脑电图光阵发性反应 (PPR)。BRV 的理化特性与 LEV 不同，具有更高的效力和亲脂性，加上对突触囊泡糖蛋白 2A 的亲和力高 10 到 15 倍。

客观的

我们使用静脉输注后 PPR 消除时间作为药效终点，比较了两种药物对光敏性癫痫患者中枢神经系统 (CNS) 的作用速度。

方法

我们使用随机、双盲、两阶段、平衡、交叉设计，在 15 分钟静脉输注后（第 1 部分）和 BRV 100 mg 静脉输注等效力毫克剂量的静脉内 LEV 1500 mg 和 BRV 100 mg 后对光敏性癫痫患者进行了测试。 5 分钟静脉输注（第 2 部分，相同剂量）。每部分 8 名患者被认为足以以 80% 的功效确定静脉内 BRV:LEV 患者体内时间比与 PPR 消除的比率减少 70%，两侧显着性水平为 0.05。使用液相色谱/质谱法测量血浆抗癫痫药浓度。

结果

9 名患者 [6 名女性；平均年龄 27.8 岁（范围 18-42）] 完成了研究；其中 7 人同时参加了第 1 部分和第 2 部分。在 32 例中的 31 例中，患者经历了 PPR 消除。在混合效应模型时间分析中，BRV 比 LEV 更快地消除了 PPR（中值分别为 2 分钟和 7.5 分钟）。然而，对于我们的多个主要结果中的两个，未观察到 BRV:LEV 时间比与 PPR 消除的统计学显着差异：单独输注 15 分钟 ( p  = 0.22) 或单独输注 5 分钟 ( p  = 0.11)。然而，当我们排除第 1 部分中的异常患者时，BRV 更快（p = 0.0016）。对于我们剩余的主要结果，即第 1 部分和第 2 部分数据的组合，患者体内 BRV:LEV 时间比的中位数为 0.39 [95% 置信区间 (CI) 0.16–0.91]，即 BRV 的 PPR 消除速度快 61%，p  = 0.039 . 11 名 BRV 患者和 4 名 LEV 患者的 PPR 在≤ 2 分钟内完全消除。没有看到期间或结转影响。没有发生严重或严重的不良反应。在消除 PPR 时（n = 16），中位血浆 [BRV] 为 250 ng/mL（范围 30–4100），中位血浆 [LEV] 为 28.35 μg/mL（范围 1–86.7）。

结论

需要直接比较 LEV 和 BRV 的结果研究来确定 BRV 反应的临床效用，BRV 比 LEV 快几分钟。

临床试验

ClinTrials.gov 标识符 = NCT03580707；注册 07-09-18