LAUSR

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 AUC0−t of active H4 and the P2Y12 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 tmax 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 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 5 mg group was slightly shorter than that in the clopidogrel 75 mg group (0.50 versus 0.75 h). The mean AUC0−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 AUC0−t of active H4 was apparently associated with the P2Y12 reaction units at 4 h for vicagrel. In the loading‐dose study, for active H4, the median tmax was slightly shorter (0.50 versus 0.75 h) and the mean AUC0−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 P2Y12 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. Trial Registration: CTR20150346, CTR20160379. Graphical abstract (A) Metabolic pathways of clopidogrel and vicagrel in humans. (B) Mean plasma concentrations of active H4 after a single oral administration of vicagrel 5 mg or clopidogrel 75 mg in healthy Chinese subjects. (C) Assessment of dose proportionality for AUC0−t of active H4 after single oral administration of vicagrel. Figure. No Caption available.