Safety, Tolerability, and Pharmacokinetics of the Monoamine Oxidase B Inhibitor, HEC122505, and its Major Metabolite After Single- and Multiple- Ascending Dose, and Food Effect Study in Healthy Chinese Subjects.

IF 1.9 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Chuanfei Jin, Chao Yi, Kangzhi Chen, Haiping Liang
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引用次数: 0

Abstract

Background and objectives: HEC122505 is a potent and selectively monoamine oxidase B inhibitor that is safe and well-tolerated in preclinical models of Parkinson's disease. The objectives of single ascending dose and multiple dose pharmacokinetic trials of HEC122505 oral tablets were to determine the safety and tolerability of HEC122505, and to examine the food effect on the pharmacokinetic parameters of HEC122505 and its major metabolite HEC129870.

Methods: The phase I study (NCT04625361) consisted of three arms: single ascending dose study (5, 20, 50, 100, 200, 300 or 400 mg HEC122505 tablets or placebo), multiple ascending dose study (20, 50 or 100 mg HEC122505 tablets or placebo once daily), and food effect (100 mg HEC122505 tablets single dose after a high-fat, high-calorie meal). All subjects completed all trial arms and were analyzed as planned.

Results: Pharmacokinetic analysis showed that HEC122505 rapidly absorbed with the time to peak plasma concentration (Tmax) ranged from 0.5 to 1.75 h. In addition, maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) increased in a dose proportional manner. Food effect study showed that a high-fat, high-calorie meal had no significant effect on the pharmacokinetics of HEC122505 and its major metabolite HEC129870, suggesting that HEC122505 could be administered in both fasted and fed state in clinical trials. The subsequent multiple-dose study evaluated doses from 20 to 100 mg dose once daily for up to 8 days. HEC122505 reached steady state after approximately 5 days with a once daily dose. In these studies, all dose of HEC122505 was generally safe and well tolerated. No grade ≥ 3 drug related adverse events (AEs) occurred.

Conclusion: HEC122505 was generally safe and well tolerated in the single ascending dose (ranging from 5 to 400 mg) and multiple ascending dose (50 to 200 mg once daily doses) studies. All the drug related adverse events (AEs) were Grade ≤ 2. There were no deaths, no subjects discontinued the trial due to AEs, and there were no other serious AEs. The safety and pharmacokinetic profile support once daily administration of HEC122505.

单胺氧化酶 B 抑制剂 HEC122505 及其主要代谢物在中国健康受试者中的安全性、耐受性和药代动力学(单剂量和多剂量服用)以及食物效应研究
背景和目的:HEC122505是一种强效选择性单胺氧化酶B抑制剂,在帕金森病临床前模型中安全且耐受性良好。HEC122505口服片剂单次升剂量和多次剂量药代动力学试验的目的是确定HEC122505的安全性和耐受性,并研究食物对HEC122505及其主要代谢物HEC129870药代动力学参数的影响:I期研究(NCT04625361)包括三个研究臂:单剂量递增研究(5、20、50、100、200、300或400毫克HEC122505片剂或安慰剂)、多剂量递增研究(20、50或100毫克HEC122505片剂或安慰剂,每日一次)和食物效应研究(100毫克HEC122505片剂在高脂肪、高热量餐后单剂量服用)。所有受试者都完成了所有试验,并按计划进行了分析:药代动力学分析表明,HEC122505吸收迅速,血浆浓度达到峰值的时间(Tmax)为0.5至1.75小时。食物效应研究表明,高脂肪、高热量膳食对HEC122505及其主要代谢物HEC129870的药代动力学无明显影响,这表明HEC122505在临床试验中可在空腹和进食状态下给药。随后进行的多剂量研究评估了 20 至 100 毫克的剂量,每天一次,最多持续 8 天。每天给药一次的 HEC122505 约在 5 天后达到稳态。在这些研究中,所有剂量的HEC122505总体安全且耐受性良好。没有发生≥3级的药物相关不良事件(AEs):结论:在单次递增剂量(5至400毫克)和多次递增剂量(50至200毫克,每日一次)研究中,HEC122505总体上安全且耐受性良好。所有与药物相关的不良事件(AEs)均≤2级。没有死亡病例,没有受试者因不良反应而中止试验,也没有其他严重不良反应。HEC122505的安全性和药代动力学特征支持每日一次给药。
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来源期刊
CiteScore
3.70
自引率
0.00%
发文量
64
审稿时长
>12 weeks
期刊介绍: Hepatology International is a peer-reviewed journal featuring articles written by clinicians, clinical researchers and basic scientists is dedicated to research and patient care issues in hepatology. This journal focuses mainly on new and emerging diagnostic and treatment options, protocols and molecular and cellular basis of disease pathogenesis, new technologies, in liver and biliary sciences. Hepatology International publishes original research articles related to clinical care and basic research; review articles; consensus guidelines for diagnosis and treatment; invited editorials, and controversies in contemporary issues. The journal does not publish case reports.
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