First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP‐ribose) Polymerase‐1 Inhibitor, JPI-289, in Healthy Volunteers

• Published in: Drug design, development and therapy Vol. 14; pp. 3189 - 3199
• Main Authors: Han, Sungpil, Kim, Yo Han, Choi, Hee Youn, Soh, Dong-Jun, Kim, Jeongmin, Nam, Joonwoo, Kim, Jong-Woo, Bae, Kyun-Seop, Lim, Hyeong-Seok
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01.01.2020; Dove; Dove Medical Press
• Subjects: Adult; Analysis; Clinical Trial Report; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Tolerance; Health aspects; healthy subject; Healthy Volunteers; Humans; Infusions, Intravenous; Ischemia; Male; Metabolites; Middle Aged; Monosaccharides; Naphthyridines - administration & dosage; Naphthyridines - adverse effects; Naphthyridines - analysis; Naphthyridines - pharmacokinetics; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - adverse effects; Neuroprotective Agents - analysis; Neuroprotective Agents - pharmacokinetics; parp-1 inhibitor; pharmacodynamics; pharmacokinetics; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - metabolism; Stroke; Young Adult; South Korea; pharmacokinetics; PARP-1 inhibitor; healthy subject; stroke; pharmacodynamics
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S235802

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. 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. In the SAD study, AUC and C tended to increase supra-proportionally especially at higher doses in SAD study. However, C showed dose-proportionality in the range of 75-600mg. JPI-289 reached a mean T within 0.50 hour after dosing and a mean elimination half-life (t ) 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. The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be useful in further clinical development of JPI-289.