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
; 127: 151-160, 2019 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-30326264
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 (5-75â¯mg) compared with clopidogrel (75â¯mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20â¯mg compared with clopidogrel 300â¯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 4â¯h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25â¯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 0.25-1.75â¯h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5-75â¯mg, with the mean Cmax and AUCs for H4 and H3 increasing in an approximately 11 dose-proportional manner and for SM3 increasing in a <11 dose-proportional manner. The median tmax for active H4 in the vicagrel 5â¯mg group was slightly shorter than that in the clopidogrel 75â¯mg group (0.50 versus 0.75â¯h). The mean AUC0-t for H4 in the vicagrel 5â¯mg group was similar to that in the clopidogrel 75â¯mg group (11.7 versus 11.8â¯ngâh/mL). The AUC0-t of active H4 was apparently associated with the P2Y12 reaction units at 4â¯h for vicagrel. In the loading-dose study, for active H4, the median tmax was slightly shorter (0.50 versus 0.75â¯h) and the mean AUC0-t was 29% higher in the vicagrel 20â¯mg group than those in the clopidogrel 300â¯mg group. After a single oral administration of vicagrel 25â¯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 5-75â¯mg. The AUC of active H4 was apparently associated with the P2Y12 reaction units for vicagrel. For active H4, vicagrel 5â¯mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75â¯mg, and vicagrel 20â¯mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300â¯mg in humans. TRIAL REGISTRATION CTR20150346, CTR20160379.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenilacetatos
/
Tiofenos
/
Inibidores da Agregação Plaquetária
/
Antagonistas do Receptor Purinérgico P2Y
/
Clopidogrel
Tipo de estudo:
Clinical_trials
Limite:
Adolescent
/
Adult
/
Humans
Idioma:
En
Revista:
Eur J Pharm Sci
Assunto da revista:
FARMACIA
/
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China