在中国健康受试者中，进行第一阶段，首次，单次和多次剂

StephenW

Clin Drug Investig. 2020 Apr 10. doi: 10.1007/s40261-020-00909-3. [Epub ahead of print]
Phase I, First-in-Human, Single and Multiple Ascending Dose- and Food-Effect Studies to Assess the Safety, Tolerability and Pharmacokinetics of a Novel Anti-hepatitis B Virus Drug, Bentysrepinine (Y101), in Healthy Chinese Subjects.
Liu X1, Xue L1, Zhang H1, Xu Q2, Zhang S2, Ma S1, Ding X1, Liu L1, Dong J1, Qian L1, Xia W3, Jiang K3, Huang C4, Miao L5,6.
Author information

1
    Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Street, Suzhou, 215006, China.
2
    Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China.
3
    Bailing Enterprise Group Pharmaceutical Co., Ltd., Guizhou, China.
4
    Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Street, Suzhou, 215006, China. [email protected].
5
    Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Street, Suzhou, 215006, China. [email protected].
6
    Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, China. [email protected].

Abstract
BACKGROUND AND OBJECTIVE:

Bentysrepinine (Y101), a derivative of repensine (a compound isolated from Dichondra repens Forst), is a novel phenylalanine dipeptide currently under development for the treatment of hepatitis B virus (HBV). The objectives of these studies were to assess the safety, tolerability and pharmacokinetics of bentysrepinine in healthy Chinese subjects.
METHODS:

Two randomised, double-blind, placebo-controlled trials evaluated a single oral dose (50-900 mg, study 01) and multiple doses (300 mg and 600 mg, study 02), and a randomised, open, crossover food-effect study (600 mg, study 03) of bentysrepinine was established. Safety and tolerability were assessed by adverse event (AE) reporting, clinical laboratory tests, physical examinations, vital sign monitoring and electrocardiogram (ECG). Plasma, urine and faecal samples were analysed using validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods to investigate the pharmacokinetics of bentysrepinine.
RESULTS:

Ninety-four subjects were enrolled, and bentysrepinine was well tolerated. Mild and reversible AEs occurred for single and multiple oral doses between 50 and 900 mg. The most common adverse effects were increased alanine aminotransferase (ALT) and aspartate transaminase (AST). Other clinically significant AEs included nausea and elevated urine leukocytes, urine red blood cells, transaminase, creatine kinase, total cholesterol, triglycerides, and low-density cholesterol. There were no clinically significant changes in the ECG, vital signs or laboratory assessments during the studies. The maximum tolerated dose (MTD) was not reached in the dose escalation study. Bentysrepinine was rapidly absorbed and metabolised with a mean time to reach maximum concentration (Tmax) between 1-2 h and a mean terminal elimination half-life (t1/2) of approximately 1-3 h. In the single ascending dose study, the exposure including the area under the concentration-time curve (AUC) and the maximum plasma concentration (Cmax) of bentysrepinine generally increased in a dose-dependent but not dose-proportional manner in the 50-900 mg dose range. The urinary excretion and faecal excretion of unchanged bentysrepinine were 2.98% and 4.58% of the total dose, respectively. In the multiple-dose study, no accumulation was found after repeated administration at the 300 mg and 600 mg dose levels. The food-effect study using a 600 mg single dose showed that food intake has an obvious effect on the absorption of bentysrepinine from tablets. No experimental differences were found based on sex.
CONCLUSION:

Bentysrepinine exhibited acceptable safety and tolerability in healthy subjects in the dose range of 50-900 mg in both single- and multiple-dose studies. The drug did not exhibit linear pharmacokinetic characteristics. No accumulation was observed after the administration of multiple 300 and 600 mg doses. Bentysrepinine is extensively metabolised in the body. Food may increase its bioavailability.
TRIALS REGISTRATION:

CFDA registration numbers CTR20160096, CTR20160094, and CTR20140543 (www.chinadrugtrials.org.cn).

PMID:
    32277364
DOI:
    10.1007/s40261-020-00909-3

StephenW

临床药物研究。 2020年4月10日。doi：10.1007 / s40261-020-00909-3。 [Epub提前发行]
在中国健康受试者中，进行第一阶段，首次，单次和多次剂量和食物效应的人体研究，以评估新型抗乙肝病毒药物Bentysrepinine（Y101）的安全性，耐受性和药代动力学。
刘X1，薛L1，张H1，徐Q2，张S2，马S1，丁X1，刘L1，董J1，钱L1，夏W3，姜K3，黄C4，苗L5，6。
作者信息

1个
苏州大学附属第一医院临床药理学教研室，苏州市平海街899号，江苏215006
2
苏州大学药学院药物系，苏州。
3
中国贵州百灵企业集团制药有限公司。
4
苏州大学附属第一医院临床药理学教研室，苏州市平海街899号，江苏215006 [email protected]。
5
苏州大学附属第一医院临床药理学教研室，苏州市平海街899号，江苏215006 [email protected]。
6
苏州大学药学院药物系，苏州。 [email protected]。

抽象
背景与目的：

Bentysrepinine（Y101）是repensine（从Dichondra repens Forst分离的化合物）的衍生物，是一种新型的苯丙氨酸二肽，目前正在开发中，用于治疗乙型肝炎病毒（HBV）。这些研究的目的是评估在中国健康受试者中苯那曲林的安全性，耐受性和药代动力学。
方法：

两项随机，双盲，安慰剂对照试验评估了单次口服剂量（50-900 mg，研究01）和多次剂量（300 mg和600 mg，研究02），以及一项随机，开放，交叉的食物效应研究建立了苯妥瑞平（600 mg，研究03）。通过不良事件（AE）报告，临床实验室测试，身体检查，生命体征监测和心电图（ECG）评估安全性和耐受性。使用经过验证的液相色谱串联质谱法（LC-MS / MS）分析血浆，尿液和粪便样品，以研究苯替米林的药代动力学。
结果：

招募了94名受试者，并且对苯妥斯匹林的耐受性良好。单次和多次口服剂量在50至900 mg之间会发生轻度和可逆的AE。最常见的不良反应是丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）升高。其他具有临床意义的不良事件包括恶心和尿液白细胞升高，尿液红细胞，转氨酶，肌酸激酶，总胆固醇，甘油三酸酯和低密度胆固醇。研究期间，心电图，生命体征或实验室评估均无临床显着变化。在剂量递增研究中未达到最大耐受剂量（MTD）。 Bentysrepinine被快速吸收并代谢，平均时间为1-2小时，达到最大浓度（Tmax），平均终末消除半衰期（t1 / 2）约为1-3小时。在单次上升剂量研究中，苯妥斯平素的浓度-时间曲线下面积（AUC）和最大血浆浓度（Cmax）下的暴露通常以剂量依赖性但不成比例的方式在50-900范围内增加毫克剂量范围。不变的苯尿曲霉碱的尿排泄和粪便排泄分别占总剂量的2.98％和4.58％。在多剂量研究中，在300 mg和600 mg剂量水平重复给药后未发现积聚。使用600毫克单剂量的食物效果研究表明，食物摄入量对片剂中苯并曲霉碱的吸收有明显影响。没有发现基于性别的实验差异。
结论：

在单剂量和多剂量研究中，在50-900 mg的剂量范围内，苯替瑞林在健康受试者中均表现出可接受的安全性和耐受性。该药物未显示线性药代动力学特征。分别服用300和600 mg剂量后未观察到积聚。 Bentysrepinine在体内广泛代谢。食物可能会增加其生物利用度。
试用注册：

CFDA注册号CTR20160096，CTR20160094和CTR20140543（www.chinadrugtrials.org.cn）。

PMID：
32277364
DOI：
10.1007 / s40261-020-00909-3

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灵魂不屈

感谢分享，这是贵州百灵那个原研药？