抗癫痫药物左乙拉西坦注射液和口服片剂在中国健康志愿者中的药动学、安全性和生物等效性研究

doi:10.5246/jcps.2018.11.078

摘要/Abstract

摘要：

左乙拉西坦(LEV)的静脉注射制剂在世界范围内的临床应用已有多年, 但在中国还没有上市。在本研究中, 我们旨在评估静脉和口服的抗癫痫药物左乙拉西坦在中国健康志愿者中的生物等效性。两个随机、单剂量(1500毫克)、开放、双周期、交叉试验按照如下方式进行: A试验: 入选健康男性受试者22例, 静脉滴注15分钟, 于口服给药和静脉滴注结束后进行血样的采集; B试验: 入选健康男性和女性受试者24例, 静脉滴注45分钟, 于口服给药和静脉滴注开始后进行血样的采集。最后对左乙拉西坦静脉注射和口服两种制剂的AUC_0-t(从0到最后可测血浆浓度的曲线下面积)、C_max(最大血浆浓度)的几何均值比及安全性进行评价。结果显示, 左乙拉西坦(1500mg)静脉滴注15分钟与口服片剂相比, AUC_0-t和C_max的90%置信区间未在80.00%～125.00%的接受范围之内, 而静脉滴注45分钟的AUC_0-t和C_max与口服片剂相比显示等效。两次试验最常见的不良反应是嗜睡, 在试验A中共有8例受试者发生了9次轻度不良反应, 在试验B中共有19例受试者发生29次轻度不良反应。由于45分钟的静脉滴注试验证实了片剂和注射液的生物等效性, 所以左乙拉西坦1500 mg的静脉注射制剂(45分钟滴注)和口服制剂具有可替换性。

关键词: 左乙拉西坦, 癫痫, 静脉注射剂型, 生物等效性, 安全性和耐受性

Abstract:

The intravenous formulation of levetiracetam (LEV) has been available in clinical practice worldwide for several years, but not in China. In the present study, we aimed to evaluate the bioequivalence of intravenous and oral LEV (tablet), an antiepileptic drug, in healthy Chinese volunteers. Two randomized, single-dose (1500 mg), open-label, 2-period crossover trials were conducted as follows: study A, 15-min infusion; study B, 45-min infusion. A total of 22 healthy men participated in study A, and 24 healthy men and woman were enrolled in study B. In study A, blood samples were collected after termination of each treatment. In study B, samples were collected after oral or after the start of the intravenous administration. Safety and the ratio of intravenous/oral LEV for AUC_0–t and C_max were evaluated. The 90% confidence intervals of C_max and AUC_0–t ratios for LEV 1500-mg tablets versus 15-min intravenous administration were outside the bioequivalence limits (80.00%–125.00%). For LEV 45-min intravenous administration, bioequivalence versus 1500-mg tablets was within the range for C_max and AUC_0–t. The most frequently adverse event (AE) was somnolence. A total of eight subjects experienced nine mild AEs in study A, and 19 subjects experienced 29 mild AEs in study B. Intravenous infusions (15 and 45 min) of 1500-mg LEV were as well tolerated as the oral tablet. Bioequivalence was demonstrated by 45-min infusions. Therefore, direct conversion from oral to intravenous LEV 1500 mg (45-min infusion), or vice versa, was possible.

Key words: Levetiracetam, Epilepsy, Intravenous formulation, Bioequivalence, Safety and tolerability

中图分类号:

R969.1

Supporting:

胡岚岚, 周娟, 邹欢, 张玥, 汤建林. 抗癫痫药物左乙拉西坦注射液和口服片剂在中国健康志愿者中的药动学、安全性和生物等效性研究 [J]. 中国药学(英文版), 2018, 27(11): 777-786.

Lanlan Hu, Juan Zhou, Huan Zou, Yue Zhang, Jianlin Tang. Pharmacokinetics, safety and bioequivalence of intravenous and oral formulations of the antiepileptic drug levetiracetam in healthy Chinese volunteers[J]. Journal of Chinese Pharmaceutical Sciences, 2018, 27(11): 777-786.

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