A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson's disease, in healthy volunteers
| Autor: | Wonsuk, Shin, Kyoung Soo, Lim, Min-Kyoung, Kim, Hyun Sook, Kim, Jihwa, Hong, Stanford, Jhee, Joseph, Kim, Sungeun, Yoo, Yeon-Tae, Chung, Jae Moon, Lee, Doo-Yeoun, Cho |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male safety Dose-Response Relationship Drug Administration Oral Parkinson Disease Drug Tolerance Drug Administration Schedule Healthy Volunteers Neuroprotective Agents first-in-human pharmacodynamics Humans Organic Chemicals KM-819 Apoptosis Regulatory Proteins pharmacokinetics Adaptor Proteins Signal Transducing Original Research |
| Zdroj: | Drug Design, Development and Therapy |
| ISSN: | 1177-8881 |
| Popis: | Background KM-819 is a novel FAS-associated factor 1 (FAF1) inhibitor, and a neuroprotective agent, under clinical development for the treatment of Parkinson’s disease as a disease-modifying drug. Methods This first-in-human, single and multiple ascending dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 in healthy volunteers. Additionally, the effect of age on safety and pharmacokinetics were assessed. The starting dose was determined considering the no observed adverse effect level based on preclinical studies, and the dose escalations in subsequent cohorts were decided based on safety, tolerability, and pharmacokinetic data from previous dose cohorts. Results After a single dose, the KM-819 plasma exposure showed a less than dose-proportional increase across a dose range of 10–400 mg. After repeated dosing, KM-819 plasma exposure increased in an approximately dose-proportional manner across the evaluated dose range (30–400 mg once daily for 7 days). The mean elimination half-life was 1.8 to 4.8 h with the lower KM-819 doses (≤30 mg), which increased to around 9 h with the higher doses (100–400 mg). When administered to the elderly population, KM-819 plasma exposure increased to 102% after a 200 mg once-daily dosing for 7 days. No clear treatment-related effects on the estimated pharmacodynamic variables were observed. Single or multiple doses of KM-819 were generally well tolerated. Conclusion The data from this study can be used to guide rational drug dosing and choose therapeutic regimens in subsequent clinical studies. |
| Databáze: | OpenAIRE |
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