药物动力学和药代动力学/药效学vicagrel关系,小说thienopyridine P2Y12抑制剂,与氯吡格雷在中国健康受试者单后口服给药。

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陆张刘C, Y,陈W, Y,李W,刘Y,赖X, Y锣,刘X, Y,陈X, X,太阳H,杨J,钟D

药物动力学和药代动力学/药效学vicagrel关系,小说thienopyridine P2Y12抑制剂,与氯吡格雷在中国健康受试者单后口服给药。

欧元J制药科学。2019年1月15;127:151 - 160。doi: 10.1016 / j.ejps.2018.10.011。Epub 2018年10月13日。

PubMed ID

30326264 (在PubMed

]

文摘

背景和目标:Vicagrel,小说thienopyridine抗血小板剂,是一种模拟的氯吡格雷治疗急性冠脉综合征的发展。本研究调查vicagrel单一口服给药后的药代动力学特性直接与氯吡格雷在健康中国受试者在前两个阶段的临床研究。之间的关系接触活性代谢物和vicagrel血小板反应性也得到了评估。研究方法:研究是一个single-ascending-dose vicagrel(5 - 75毫克)与氯吡格雷(75毫克)的67名健康志愿者。研究B是一个随机、两年期、交叉负荷剂量的研究vicagrel 20毫克与氯吡格雷在12个健康受试者300毫克。等离子体浓度的三种常见的代谢物vicagrel和氯吡格雷,活跃的硫醇代谢物H4,不活跃的硫醇代谢物H3, H3的S-methylated形式(SM3 vicagrel的主要代谢物),确定使用UHPLC-MS / MS方法进行验证。活动H4的AUC0-t之间的关系和P2Y12反应单位4 h vicagrel管理局调查后。vicagrel血药浓度的测定单一vicagrel 25毫克口服后两个健康中国受试者。结果:在single-ascending-dose研究中,vicagrel代谢迅速的平均最高温度三个代谢物,即H4, H3, SM3,从0.25 - -1.75 h。三种代谢物的药物代谢动力学vicagrel线性在5 - 75毫克的剂量范围,意味着Cmax和auc的H4和H3增加约1:1 dose-proportional方式和SM3增加< 1:1 dose-proportional的方式。 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
Vicagrel	P2Y purinoceptor 12	蛋白质	人类	未知的	拮抗剂 抑制剂	细节