Erratum: Safety, Tolerability and Pharmacokinetics of MCI-186 in Patients with Acute Ischemic Stroke: New Formulation and Dosing Regimen

Background and Purpose: MCI-186 (edaravone) is a free radical scavenger approved in Japan since 2001 for the treatment of patients with acute ischemic stroke within 24 h from the onset of symptoms. It was recommended by the Japanese Guidelines for the Management of Stroke 2004. Our aim was to investigate the safety, tolerability and pharmacokinetics of a new formulation and dose regimen (intravenous bolus plus infusion) of MCI-186 suitable for the treatment of acute ischemic stroke in Europe because the Japanese treatment protocol includes twice-a-day intravenous infusion of MCI-186 for a maximum of 14 days. Such a treatment protocol is not very practical in Europe, where hospital stay is much shorter in acute hospitals. Methods: In a double-blind, placebo-controlled randomized clinical trial we studied two dosing regimens, each in a cohort of 18 patients. Patients were randomized in a 2:1 ratio in both cohorts to receive MCI-186 or placebo. Review of safety and plasma concentration data from the first cohort (loading dose 0.08 mg/kg + 0.2 mg/kg/h infusion) preceded the second cohort (loading dose 0.16 mg/kg + 0.4 mg/kg/h infusion). Safety parameters included adverse events, severe adverse events, physical examinations, local reactions at infusion site, ECG, clinical chemistry and hematology, modified Total Neuropathy Score and CT scans. Results: Mean age and National Institutes of Health Stroke Scale (NIHSS) score on admission of patients in cohorts 1 and 2 and the placebo group were 64, 63, and 69 years and 5, 5, and 6, respectively. The number of treatment emergent adverse events that occurred was 109, most of which were transient, mild or moderate. Both doses of the new formulation and dosing regimen were well tolerated. After the initiation of the infusion, plasma concentrations of MCI-186 reached or exceeded prespecified target levels within 24 h in both MCI-186 cohorts, which were in the putative therapeutic range in humans. Geometric mean values of MCI-186 plasma concentration at the end of the infusion in cohorts 1 and 2 were 391 and 1,595 ng/ml, respectively. Conclusions: The primary objective of the present study, safety and tolerability of the new formulation and dosing regimen, was achieved. The new formula and both dosing regimens were well tolerated and achieved intended plasma concentrations suitable for larger safety studies before pivotal trials.

背景与目的：MCI-186（依达拉奉，edaravone）是一种自由基清除剂，自2001年起在日本获批用于症状发作24小时内的急性缺血性脑卒中患者治疗，并被《2004年日本脑卒中管理指南》所推荐。鉴于日本的治疗方案为每日两次静脉输注MCI-186，最长持续14天，而欧洲急性医院的住院时长普遍较短，该方案在欧洲的临床实用性欠佳。本研究旨在探索适用于欧洲急性缺血性脑卒中治疗的MCI-186新剂型与给药方案（静脉弹丸注射联合输注）的安全性、耐受性及药代动力学特征。
方法：本研究采用双盲、安慰剂对照随机临床试验设计，设置两个给药方案队列，每个队列纳入18例患者。两个队列均以2:1的比例随机分配至MCI-186组或安慰剂组。首个队列采用负荷剂量0.08 mg/kg + 0.2 mg/kg/h的输注方案，基于该队列的安全性及血浆浓度数据，对第二个队列（负荷剂量0.16 mg/kg + 0.4 mg/kg/h输注）的给药方案进行了优化调整。安全性评价指标包括不良事件、严重不良事件、体格检查、输注部位局部反应、心电图、临床生化与血液学检查、改良总体神经病学评分以及计算机断层扫描（Computed Tomography, CT）扫描。
结果：队列1、队列2及安慰剂组患者的平均年龄分别为64岁、63岁与69岁，入院时美国国立卫生研究院卒中量表（National Institutes of Health Stroke Scale, NIHSS）评分分别为5分、5分及6分。本研究共记录到109例治疗中出现的不良事件，其中多数为一过性、轻度或中度反应。两种剂量的新剂型与给药方案均具有良好的耐受性。输注启动后，两个MCI-186队列的血浆MCI-186浓度均在24小时内达到或超过预设靶标浓度，处于推定的人体治疗浓度范围内。队列1和队列2在输注结束时的MCI-186血浆浓度几何均值分别为391 ng/ml和1595 ng/ml。
结论：本研究的主要研究终点——新剂型与给药方案的安全性与耐受性已达成。新配方及两种给药方案均具有良好的耐受性，且达到了预期的血浆浓度水平，可用于关键临床试验前的更大规模安全性研究。