First-in-Human Evaluation of the Safety, Tolerability, and Pharmacokinetics of a Neuroprotective Poly (ADP‐ribose) Polymerase‐1 Inhibitor, JPI-289, in Healthy Volunteers
| Autor: | Hyeong-Seok Lim, Hee Youn Choi, Kyun-Seop Bae, Kim Jongwoo, Yo Han Kim, Kim Jeongmin, Joonwoo Nam, Sungpil Han, Dong-Jun Soh |
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| Rok vydání: | 2020 |
| Předmět: |
Adult
Male 0301 basic medicine Poly (ADP-Ribose) Polymerase-1 Cmax Pharmaceutical Science healthy subject Urine Pharmacology Placebo Drug Administration Schedule Young Adult 03 medical and health sciences 0302 clinical medicine Double-Blind Method Pharmacokinetics Drug Discovery pharmacodynamics Humans Medicine Dosing Naphthyridines Infusions Intravenous Adverse effect Dose-Response Relationship Drug business.industry Drug Tolerance Middle Aged PARP-1 inhibitor stroke Healthy Volunteers Neuroprotective Agents 030104 developmental biology Tolerability Clinical Trial Report 030220 oncology & carcinogenesis Pharmacodynamics business pharmacokinetics |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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