Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y(12) inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing

doi:10.1016/j.ejps.2018.10.011

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 上海药物代谢研究中心

	Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y(12) inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing
	Li, Cai 7; Zhang, Yifan7 ; Chen, Weili 1; Lu, Youming 7; Li, Wei 7; Liu, Yongqiang 2; Lai, Xiaojuan 2; Gong, Yanchun 2; Liu, Xuefang 2; Li, Yongguo 3
刊名	EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
	2019-01-15
卷号	127 页码:151-160
关键词	Vicagrel Clopidogrel P2Y(12) inhibitor Pharmacokinetics Active metabolite Thienopyridine
ISSN号	0928-0987
DOI	10.1016/j.ejps.2018.10.011
文献子类	Article
英文摘要	Background and objectives: Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel. Methods: Study A was a single-ascending-dose study of vicagrel (5-75 mg) compared with clopidogrel (75 mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20 mg compared with clopidogrel 300 mg in 12 healthy subjects. Plasma concentrations of three common metabolites of vicagrel and clopidogrel, the active thiol metabolite H4, the inactive thiol metabolite H3, and the S-methylated form of H3 (SM3, the major metabolite of vicagrel), were determined using a validated UHPLC-MS/MS method. The relationship between the AUC(0-t) of active H4 and the P2Y(12) reaction units at 4 h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25 mg to two healthy Chinese subjects. Results: In the single-ascending-dose study, vicagrel was metabolized rapidly with the median t(max) for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25-1.75 h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5-75 mg, with the mean C-max and AUCs for H4 and H3 increasing in an approximately 1:1 dose-proportional manner and for SM3 increasing in a < 1:1 dose-proportional manner. The median t(max) for active H4 in the vicagrel 5 mg group was slightly shorter than that in the clopidogrel 75 mg group (0.50 versus 0.75 h). The mean AUC(0-t) for H4 in the vicagrel 5 mg group was similar to that in the clopidogrel 75 mg group (11.7 versus 11.8 ng.h/mL). The AUC(0-t) of active H4 was apparently associated with the P2Y(12) reaction units at 4 h for vicagrel. In the loading-dose study, for active H4, the median tma was slightly shorter (0.50 versus 0.75 h) and the mean AUC(0)(-t) was 29% higher in the vicagrel 20 mg group than those in the clopidogrel 300 mg group. After a single oral administration of vicagrel 25 mg to 2 subjects, vicagrel was detected in blood but in very low concentrations. Conclusions: Vicagrel was rapidly and extensively metabolized, and the levels of the parent drug in circulation were very low. The pharmacokinetics of the three metabolites of vicagrel were linear and predictable across the dose range of 5-75 mg. The AUC of active H4 was apparently associated with the P2Y(12) reaction units for vicagrel. For active H4, vicagrel 5 mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75 mg, and vicagrel 20 mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300 mg in humans.
资助项目	Jiangsu Vcare PharmaTech Co., Ltd.[00000000] ; China Pharmaceutical University[00000000] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing program" of China[2013ZX09301303] ; National Natural Science Foundation of China[81521005] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306]
WOS关键词	ST-SEGMENT ELEVATION ; ACTIVE METABOLITE ; MYOCARDIAL-INFARCTION ; THIOL METABOLITE ; MS/MS METHOD ; PRASUGREL ; PHARMACODYNAMICS ; DISPOSITION ; ACTIVATION ; RESISTANCE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000453000000016
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279457]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Li, Xuening; Sun, Hongbin; Yang, Jin; Zhong, Dafang
作者单位	1.Fudan Univ, Zhongshan Hosp, Dept Clin Pharmacol, Shanghai 200032, Peoples R China; 2.Jiangsu Vcare PharmaTech Co Ltd, 15 Wanshou Rd, Nanjing 211800, Jiangsu, Peoples R China; 3.Hua Med Shanghai Ltd, 275 Ai Di Sheng Rd, Shanghai 201203, Peoples R China; 4.China Pharmaceut Univ, Coll Pharm, State Key Lab Nat Med, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 5.China Pharmaceut Univ, Coll Pharm, Ctr Drug Discovery, 24 Tongjia Xiang, Nanjing 210009, Jiangsu, Peoples R China; 6.China Pharmaceut Univ, Ctr Drug Metab & Pharmacokinet, Nanjing 210009, Jiangsu, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Li, Cai,Zhang, Yifan,Chen, Weili,et al. Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y(12) inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing[J]. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,2019,127:151-160.
APA	Li, Cai.,Zhang, Yifan.,Chen, Weili.,Lu, Youming.,Li, Wei.,...&Zhong, Dafang.(2019).Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y(12) inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing.EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES,127,151-160.
MLA	Li, Cai,et al."Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y(12) inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing".EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES 127(2019):151-160.