Yoshinaga Harumi, Benitez Arturo, Takeda Shinichi, Fournier Martha, Kugler Alan R
National Hospital Organization Minami-Okayama Medical Center, Okayama, Japan.
Takeda Pharmaceuticals, Cambridge, MA, USA.
Epilepsy Res. 2021 Aug;174:106651. doi: 10.1016/j.eplepsyres.2021.106651. Epub 2021 May 5.
In Japan, intravenous (IV) administration of antiepileptic drugs in a healthcare setting is the preferred treatment option that is both licensed and recommended for initial treatment of status epilepticus (SE). However, prompt conveyance to a healthcare institution and IV access may be difficult in patients experiencing a seizure and so delay treatment. Thus, there is an unmet need for an alternative effective antiepileptic drug with an easier and more rapid mode of administration. In this study we evaluated a midazolam hydrochloride oromucosal solution (MHOS) that can be simply and rapidly administered to patients in SE.
A Phase 3, interventional, multicenter, nonrandomized study was conducted in 28 clinical centers in Japan. Pediatric subjects in convulsive SE received treatment with buccal MHOS with dosage based on their age. The primary efficacy outcome was the percentage of subjects with seizure termination within 10 min and a 30-min absence of visible seizure activity from time of administration. Safety evaluations included respiratory depression and the frequency of treatment-emergent adverse events (TEAEs). Pharmacokinetic (PK) profile was also assessed.
The study population comprised 25 subjects with a median age of 2.8 years and median bodyweight of 13.4 kg. The primary efficacy outcome was achieved in 80 % of subjects; 84 % of subjects had seizure resolution within 10 min. Nine subjects experienced a total of 13 TEAEs, and protocol-defined respiratory depression occurred in one subject. Mean maximum plasma midazolam concentration was 78.0 ng/mL, and mean time to peak concentration was 20.5 min, demonstrating that achieving maximum plasma midazolam concentration is not required for seizure cessation.
The efficacy, safety and pharmacokinetic profile of MHOS in pediatric Japanese subjects was consistent with that observed in non-Japanese populations. Compared to IV treatments, MHOS offers easier administration which may reduce the time to treatment and thereby minimize the sequelae of prolonged seizures.
在日本，在医疗机构中静脉注射抗癫痫药物是治疗癫痫持续状态（SE）初始治疗的首选方案，该方案既有许可又被推荐。然而，对于癫痫发作的患者来说，迅速转运至医疗机构并建立静脉通路可能很困难，从而延误治疗。因此，对于一种给药方式更简便、更快速的替代有效抗癫痫药物存在未满足的需求。在本研究中，我们评估了一种可简单快速地给予SE患者的盐酸咪达唑仑口腔黏膜溶液（MHOS）。
在日本的28个临床中心进行了一项3期、干预性、多中心、非随机研究。惊厥性SE的儿科受试者接受颊部MHOS治疗，剂量根据其年龄确定。主要疗效指标是在给药后10分钟内癫痫发作终止且30分钟内无可见癫痫活动的受试者百分比。安全性评估包括呼吸抑制和治疗中出现的不良事件（TEAE）的发生率。还评估了药代动力学（PK）特征。
研究人群包括25名受试者，中位年龄为2.8岁，中位体重为13.4千克。80%的受试者达到主要疗效指标；84%的受试者在10分钟内癫痫发作得到缓解。9名受试者共经历了13次TEAE，1名受试者出现了方案定义的呼吸抑制。咪达唑仑血浆平均最大浓度为78.0 ng/mL，平均达峰时间为20.5分钟，表明癫痫停止发作并不需要达到咪达唑仑血浆最大浓度。
MHOS在日本儿科受试者中的疗效、安全性和药代动力学特征与在非日本人群中观察到的一致。与静脉注射治疗相比，MHOS给药更简便，这可能会缩短治疗时间，从而将长时间癫痫发作的后遗症降至最低。
