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首页> 外文期刊>Drug Design, Development and Therapy >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
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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

机译：一项针对人类志愿者的研究，旨在研究帕金森氏病药物KM-819（FAS相关因子1抑制剂）的安全性，耐受性，药代动力学和药效学

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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.
机译：背景：KM-819是一种新型的FAS相关因子1（FAF1）抑制剂，也是一种神经保护剂，正在临床开发中，可作为治疗疾病的帕金森氏病治疗。方法：这项首次在人体中进行的单次和多次递增剂量研究研究了KM-819在健康志愿者中的安全性，耐受性，药代动力学和药效学。此外，评估了年龄对安全性和药代动力学的影响。在临床前研究的基础上，考虑到未观察到的不良反应水平，确定起始剂量，并根据安全性，耐受性和先前剂量组的药代动力学数据确定后续队列中的剂量递增。结果：单剂给药后，KM-819血浆暴露在10–400？mg剂量范围内显示小于剂量比例的增加。重复给药后，在评估的剂量范围内（每天7–30毫克，每天一次），KM-819血浆暴露以近似剂量比例的方式增加。较低的KM-819剂量（≤30 mg）的平均消除半衰期为1.8至4.8 h，而较高的剂量（100-400 mg）则增加至约9 h。当对老年人群给药时，每天一次200毫克给药7天后，KM-819血浆暴露增加至102％。没有观察到与估计的药效学变量有关的明确治疗相关作用。单剂或多剂KM-819通常耐受良好。结论：本研究的数据可用于指导合理的药物剂量和在随后的临床研究中选择治疗方案。

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