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首页> 外文期刊>Drug Design, Development and Therapy >First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP‐ribose) Polymerase‐1 Inhibitor, JPI-289, in Healthy Volunteers
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First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP‐ribose) Polymerase‐1 Inhibitor, JPI-289, in Healthy Volunteers

机译：首先对健康志愿者进行神经保护酶（ADP-核糖）聚合酶-1抑制剂，JPI-289的安全性，耐受性和药代动力学的第一单人评价

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Background: Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor has therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. In this first-in-human study, we investigate the safety, tolerability and pharmacokinetics (PK) of JPI-289 in healthy male volunteers. Subjects and Methods: In single ascending dose (SAD) study, 35, 75, 150, 300, 600 mg JPI-289 or placebo was infused intravenously over 30 minutes to 40 subjects. In multiple ascending dose (MAD) study, 150, 300, 450 mg JPI-289 or placebo was infused over 1 hour every 12 hours to each of 24 subjects for 3.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined. Results: In the SAD study, AUClast and Cmax tended to increase supra-proportionally especially at higher doses in SAD study. However, Cmax showed dose-proportionality in the range of 75– 600mg. JPI-289 reached a mean Tmax within 0.50 hour after dosing and a mean elimination half-life (t1/2) was 2.18 to 3.21 hours. In the MAD study, observed accumulation index ranged from 1.52 to 1.76. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that the plasma JPI-289 concentration rapidly reaches steady state. % recovered of JPI-289 measured in urine was 1.59– 9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Adverse events reported in the study were all mild in intensity and resolved without any sequelae. Conclusion: The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.
机译：背景：聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂通过抑制小胶质激活和促进​​神经保护术而急性缺血性卒中具有治疗潜力。在这个先进的研究中，我们研究了JPI-289在健康男性志愿者中的安全性，耐受性和药代动力学（PK）。受试者和方法：在单一升序剂量（悲伤）研究中，35,75,150,300,600mg JPI-289或安慰剂静脉注射30分钟至40个受试者。在多个上升剂量（疯狂）的研究中，150,300,450mg JPI-289或安慰剂每12小时再注入1小时，每12小时，每12小时均为3.5天（7次）。确定了JPI-289的血浆和尿液浓度及其代谢物。结果：在悲伤的研究中，Auclast和Cmax倾向于比例地增加了悲伤的研究中的较高剂量。然而，CMAX显示在75-600mg范围内的剂量比例。 JPI-289在给药后0.50小时内达到平均Tmax，平均消除半衰期（T1 / 2）为2.18至3.21小时。在疯狂的研究中，观察到的积累指数范围为1.52至1.76。 JPI-289的有效半衰期为1.88至3.05小时，表明血浆JPI-289浓度迅速达到稳定状态。尿液中测量的JPI-289恢复的％是1.59-9.05％。在这两种研究中，代谢物的浓度小于JPI-289的10％。研究中报告的不良事件全部温和，并且没有任何后遗症解决。结论：在这些研究中评估JPI-289的可耐受剂量范围和药代动力学特征将在JPI-289的进一步临床开发中有用。

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