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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.
Drug Design, Development and Therapy ( IF 4.7 ) Pub Date : 2020-08-05 , DOI: 10.2147/dddt.s235802
Sungpil Han 1 , Yo Han Kim 1 , Hee Youn Choi 1 , Dong-Jun Soh 2 , Jeongmin Kim 2 , Joonwoo Nam 2 , Jong-Woo Kim 2 , Kyun-Seop Bae 1 , Hyeong-Seok Lim 1
Affiliation  

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.



中文翻译:

对健康志愿者中神经保护性聚(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首次人体评估。

背景:聚(ADP-核糖)聚合酶-1(PARP-1)抑制剂通过抑制小胶质细胞活化和促进神经保护具有治疗急性缺血性卒中的潜力。在这项首次人体研究中,我们调查了 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:在单次递增剂量 (SAD) 研究中,35、75、150、300、600 mg JPI-289 或安慰剂在 30 分钟内静脉内输注给 40 名受试者。在多次递增剂量 (MAD) 研究中,150、300、450 mg JPI-289 或安慰剂在 1 小时内每 12 小时向 24 名受试者中的每人输注 3.5 天(7 次)。测定了 JPI-289 及其代谢物的血浆和尿液浓度。
结果:在 SAD 研究中,AUC最后在 SAD 研究中,尤其是在较高剂量时,C max趋于成比例地增加。然而,C max在 75–600mg 范围内显示出剂量比例性。JPI-289 在给药后 0.50 小时内达到平均 Tmax 平均消除半衰期 (t 1/2 ) 为 2.18 至 3.21 小时。在 MAD 研究中,观察到的累积指数范围为 1.52 至 1.76。JPI-289的有效半衰期为1.88~3.05小时,表明血浆JPI-289浓度迅速达到稳态。在尿液中测得的 JPI-289 回收率为 1.59–9.05%。在这两项研究中,代谢物的浓度低于 JPI-289 的 10%。研究中报告的不良事件的强度均较轻,并且在没有任何后遗症的情况下得到解决。
结论:在这些研究中评估的 JPI-289 的耐受剂量范围和药代动力学特征将有助于 JPI-289 的进一步临床开发。

更新日期:2020-08-05
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