Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing.

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Liu C, Zhang Y, Chen W, Lu Y, Li W, Liu Y, Lai X, Gong Y, Liu X, Li Y, Chen X, Li X, Sun H, Yang J, Zhong D

Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing.

Eur J Pharm Sci. 2019 Jan 15;127:151-160. doi: 10.1016/j.ejps.2018.10.011. Epub 2018 Oct 13.

PubMed ID
30326264 [ View in PubMed
]
Abstract

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 (5-75mg) compared with clopidogrel (75mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20mg compared with clopidogrel 300mg 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 AUC0-t of active H4 and the P2Y12 reaction units at 4h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25mg to two healthy Chinese subjects. RESULTS: In the single-ascending-dose study, vicagrel was metabolized rapidly with the median tmax for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25-1.75h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5-75mg, with the mean Cmax 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 tmax for active H4 in the vicagrel 5mg group was slightly shorter than that in the clopidogrel 75mg group (0.50 versus 0.75h). The mean AUC0-t for H4 in the vicagrel 5mg group was similar to that in the clopidogrel 75mg group (11.7 versus 11.8ngh/mL). The AUC0-t of active H4 was apparently associated with the P2Y12 reaction units at 4h for vicagrel. In the loading-dose study, for active H4, the median tmax was slightly shorter (0.50 versus 0.75h) and the mean AUC0-t was 29% higher in the vicagrel 20mg group than those in the clopidogrel 300mg group. After a single oral administration of vicagrel 25mg 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 5-75mg. The AUC of active H4 was apparently associated with the P2Y12 reaction units for vicagrel. For active H4, vicagrel 5mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75mg, and vicagrel 20mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300mg in humans. TRIAL REGISTRATION: CTR20150346, CTR20160379.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
VicagrelP2Y purinoceptor 12ProteinHumans
Unknown
Antagonist
Inhibitor
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