A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS-986231 in Healthy Volunteers
A Phase 1 Randomized Study of Single Intravenous Infusions of the Novel Nitroxyl Donor BMS-986231 in Healthy Volunteers
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DOI：
10.1002/jcph.1364
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发表时间：
2019-05-01
影响因子：
2.9
通讯作者：
Foo, Shi Yin
中科院分区：
文献类型：
--
作者：
Cowart, Douglas;Venuti, Robert P.;Foo, Shi Yin
氮氧基(HNO)是一种活性氮分子，对急性心力衰竭患者具有潜在的治疗作用。报告了一种新的HNO供体BMS-986231的首次人体研究结果。这项序贯队列研究的目的是评估健康志愿者在24小时和48小时静脉输注BMS-986231后的安全性、耐受性和药代动力学特征。对80名受试者进行了随机分组和给药。7个队列(A层)接受BMS-986231 0.10、0.33、1、3、5、10和15微克/公斤/分钟或安慰剂，24小时内输注。另一组(B层)接受超过48小时的10微克/公斤/分钟或安慰剂。在输液完成后30天内报告不良事件(AE)。定期采集血/尿样本；还评估了其他参数(血压、心率/节律、心脏指数)。在接受BMS-986231治疗的患者中，头痛是最常见的与药物相关的AE(48%)，尽管其严重程度通过水合作用得到缓解。没有发现其他与毒品有关的重大不良反应。与基线相比，BMS-986231与剂量依赖性和耐受性良好的收缩压和舒张压的降低有关；非侵入性测量的心脏指数增加。BMS-986231对心率/节律或实验室参数无临床显著影响。平均消除半衰期为0.7~2.5小时。BMS-986231是安全和耐受性良好的，可持续24小时(15微克/公斤/分钟)或48小时(10微克/公斤/分钟)，并观察到良好的血流动力学特征。正在进行的研究继续评估BMS-986231在急性心力衰竭患者中的潜在益处。
Nitroxyl (HNO) is a reactive nitrogen molecule that has potential therapeutic benefits for patients with acute heart failure. The results of the first-in-human study for BMS-986231, a novel HNO donor, are reported. The aim of this sequential cohort study was to evaluate the safety, tolerability, and pharmacokinetic profile of BMS-986231 after 24- and 48-hour intravenous infusions in healthy volunteers. Eighty subjects were randomized and dosed. Seven cohorts (stratum A) received BMS-986231 0.1, 0.33, 1, 3, 5, 10, and 15 mu g/kg/min or placebo, infused over 24 hours. An additional cohort (stratum B) received 10 mu g/kg/min or placebo, infused over 48 hours. Adverse events (AEs) were reported for 30 days after completion of infusion. Blood/urine samples were collected at regular intervals; other parameters (blood pressure, heart rate/rhythm, cardiac index) were also assessed. Headaches were the most commonly reported drug-related AE (48%) in those who received BMS-986231, although their severity was reduced by hydration. No other significant drug-related AEs were noted. BMS-986231 was associated with dose-dependent and well-tolerated reductions in systolic and diastolic blood pressure versus baseline; cardiac index, as measured noninvasively, was increased. BMS-986231 had no clinically significant effect on heart rate/rhythm or laboratory parameters. Its mean elimination half-life was 0.7-2.5 hours. BMS-986231 was safe and well-tolerated for up to 24 hours (15 mu g/kg/min) or 48 hours (10 mu g/kg/min), with a favorable hemodynamic profile observed. Ongoing studies continue to evaluate the potential benefit of BMS-986231 in patients with acute heart failure.