Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies
Pharmacokinetics, Safety, Tolerability, and Pharmacodynamics of Alicapistat, a Selective Inhibitor of Human Calpains 1 and 2 for the Treatment of Alzheimer Disease: An Overview of Phase 1 Studies
复制标题
DOI：
10.1002/cpdd.598
复制
发表时间：
2019-04-01
影响因子：
2
通讯作者：
Rendenbach-Mueller, Beatrice
中科院分区：
文献类型：
--
作者：
Lon, Hoi-Kei;Mendonca, Nuno;Rendenbach-Mueller, Beatrice
Alicapistat是一种口服活性的钙蛋白酶1和2的选择性抑制剂，其过度激活与阿尔茨海默病(AD)有关。三项研究是在健康受试者(18-55岁)中进行的，一项研究是在健康老年人(65岁)中进行的，还有一项研究是在轻中度AD患者中进行的。四项研究评估了药代动力学，1项健康受试者评估了药效学(睡眠参数，特别是快速眼动[REM]，作为衡量中枢神经系统[CNS]渗透和活动的指标)，所有研究都评估了安全性。参与者接受单剂或多剂每日两次的阿利卡司他，最长可达14天。最大血药浓度在服药后2~5小时内达到，半衰期为7~12小时。Alicapistat暴露在Alicapistat 50-1000 mg剂量范围内与剂量成比例。在健康的年轻人和老年受试者以及AD患者中，暴露于联苯双酯R，S非对映异构体的剂量大约是接触R，R非对映异构体的2倍。每日两次400或800毫克的阿利卡匹特对REM睡眠参数没有影响，而主动对照组，每天两次10毫克的多奈哌齐影响睡眠参数。在所有试验中，安慰剂组和阿利卡匹坦组的紧急不良事件发生率相似。生命体征和实验室测量在临床上没有显著变化。缺乏对睡眠的影响表明，中枢神经系统中的浓度不够高，或者临床前研究没有预测出对人类的影响。
Alicapistat is an orally active selective inhibitor of calpain 1 and 2 whose overactivation has been linked to Alzheimer disease (AD). Three studies were conducted in healthy subjects (18-55 years), 1 in healthy elderly subjects (>= 65 years), and 1 in patients with mild to moderate AD. Four studies assessed pharmacokinetics, 1 study in healthy subjects assessed pharmacodynamics (sleep parameters, particularly rapid eye movement [REM], as a measure of central nervous system [CNS] penetration and activity), and all studies assessed safety. Participants received single doses or multiple twice-daily doses of alicapistat for up to 14 days. Maximum alicapistat plasma concentrations were reached in 2 to 5 hours; half-life was 7 to 12 hours postdose. Alicapistat exposure was dose proportional in the alicapistat 50- to 1000-mg dose range. Exposure of the alicapistat R,S diastereomer was approximately 2-fold greater than exposure of the R,R diastereomer in healthy young and elderly subjects and patients with AD. Alicapistat at 400- or 800-mg twice-daily doses had no effect on REM sleep parameters, whereas the active control, donepezil at 10 mg twice daily, affected sleep parameters. Across all trials, the incidence of treatment-emergent adverse events was similar in the placebo and alicapistat groups. There were no clinically significant changes in vital signs and laboratory measurements. The lack of an effect of alicapistat on sleep suggests that concentrations in the CNS were inadequate or that preclinical studies do not predict alicapistat effects in humans.