Belousova E D
Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(8):32-8.
Despite availability of many AEDs, failure rate of first AED used in children with newly diagnosed epilepsy remains as high as 20-40%. Although likelihood of seizure freedom declines with successive AEDs, almost 1 in 5 patients become seizure free with the addition of an alternative AED after failure of 2-5 agents. New AED - perampanel (PER) was developed as a selective, non-competitive AMPA receptor antagonist to target post-synaptic glutamate transmission.
Efficacy and tolerability of PER in adolescents and adults with refractory partial seizures secondarily generalized and without generalization was assessed in international (global) randomized placebo-controlled prospective phase III trials with prolonged open follow-up phase. 1478 patients aged older than 12 years were included. All of them were unsuccessfully pretreated with 1-3 AEDs. Patients were randomized either to placebo or to 2, 4, 8, 12 mg of PER daily respectively. After completing the double blind phase they were transferred to open extension phase with titration of daily dose of PER up to 12 mg.
PER in doses of 4, 8, and 12 mg/day provided reductions in the frequency of partial-onset seizures compared with placebo. Percentage of patients achieving ≤ 50% reduction from baseline in seizure frequency/28 days on doses 4, 8 and 12 mg daily was 29%, 35% and 35% respectively vs. 19% in placebo group (p<0,01). Median% change from baseline in seizure frequency/28 days saw also more evident in PER group. Adverse events (AEs) occurred in 65-89% of patients receiving any dose of PER vs. 67% patients receiving placebo. Most AEs were of mild or moderate intensity (dose related). Most frequently reported AEs were dizziness, somnolence and aggression. 1218 pts were enrolled in the open-label extension study. 91% of patients reached 10 or 12 mg/day of PER. Efficacy was maintained with long-term treatment with responder rates of 62.7% during Weeks 92-104. Frequency and character of AEs were consistent with that in double blind phase.
The presented data indicate that PER at a daily dose of 4, 8 or 12 mg is efficacious as additional treatment of adolescents and adults with refractory partial seizures secondarily generalized and without generalization with acceptable tolerability.
尽管有多种抗癫痫药物（AEDs）可供使用，但新诊断癫痫患儿首次使用AED的失败率仍高达20%-40%。虽然随着后续AEDs的使用，无癫痫发作的可能性会降低，但在2-5种药物治疗失败后，每5名患者中仍有近1名通过加用另一种AED实现无癫痫发作。新型AED——吡仑帕奈（PER）是作为一种选择性、非竞争性α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂开发的，旨在靶向突触后谷氨酸传递。
在国际（全球）随机、安慰剂对照、前瞻性III期试验及延长的开放随访阶段中，评估了PER对继发全身性发作且无全身性发作的难治性部分性发作青少年和成人的疗效及耐受性。纳入了1478名年龄大于12岁的患者。他们全部接受过1-3种AEDs治疗但未成功。患者被随机分为安慰剂组或分别每日服用2、4、8、12mg的PER组。完成双盲阶段后，他们转入开放延长期，将PER的每日剂量滴定至12mg。
与安慰剂相比，每日剂量为4、8和12mg的PER可降低部分性发作的频率。每日服用4、8和12mg剂量时，癫痫发作频率/28天较基线降低≤50%的患者百分比分别为29%、35%和35%，而安慰剂组为19%（p<0.01）。癫痫发作频率/28天较基线的中位数变化百分比在PER组也更明显。接受任何剂量PER的患者中65%-89%发生不良事件（AEs），接受安慰剂的患者中这一比例为67%。大多数AEs为轻度或中度（与剂量相关）。最常报告的AEs为头晕、嗜睡和攻击行为。1218名患者参加了开放标签延长期研究。91%的患者达到了每日10或12mg的PER剂量。长期治疗可维持疗效，在第92-104周时缓解率为62.7%。AEs的频率和特征与双盲阶段一致。
所呈现的数据表明，每日剂量为
