Drug Design, Development and Therapy (Aug 2020)
First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP‐ribose) Polymerase‐1 Inhibitor, JPI-289, in Healthy Volunteers
Abstract
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 Lim1 1Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 2Clinical Development Team, Jeil Pharmaceutical Co. Ltd, Seoul, Republic of KoreaCorrespondence: Hyeong-Seok LimDepartment of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul 05505, Republic of KoreaTel +82-2-3010-4623Fax +82-2-3010-4622Email [email protected]: 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.Keywords: stroke, pharmacokinetics, pharmacodynamics, healthy subject, PARP-1 inhibitor
