在不同CYP 2C19基因分型患者中比较维卡格雷和氯吡格雷的抗血小板作用  

Comparison of the antiplatelet effects between vicagrel and clopidogrel in patients with different cytochrome P4502C19 genotypes

作　　者：曹伊楠 祁子钊 任玲 李晶 裘淼涵 王可心 孙宏斌[2] 龚彦春 李毅 韩雅玲 Cao Yinan;Qi Zizhao;Ren Ling;Li Jing;Qiu Miaohan;Wang Kexin;Sun Hongbin;Gong Yanchun;Li Yi;Han Yaling(Department of Cardiology,General Hospital of Northern Theater Command,Shenyang 110016,China;Chongqing Innovation Institute,China Pharmaceutical University,Chongqing 401135,China;Department,Jiangsu Vcare Pharma Tech Co.,Ltd,Nanjing 211800,China)

机构地区：[1]解放军北部战区总医院心内科,沈阳110016 [2]重庆中国药科大学创新研究院,重庆401135 [3]江苏威凯尔医药科技有限公司研发部,南京211800

出　　处：《中华心血管病杂志》2024年第5期493-499,共7页Chinese Journal of Cardiology

摘　　要：目的比较维卡格雷和氯吡格雷在不同细胞色素P450(CYP)2C19基因型患者中的抗血小板作用。方法本研究为维卡格雷Ⅱ期临床研究的事后分析。维卡格雷的Ⅱ期临床研究于2018年8月至2019年6月在国内18家中心纳入接受经皮冠状动脉介入治疗的冠心病患者。按照是否携带CYP 2C19*2或*3功能缺失(LOF)等位基因将患者分为LOF携带组(111例)和非LOF携带组(90例);以上两组中,按治疗方案又分别分为维卡格雷5 mg组、维卡格雷6 mg组、维卡格雷7.5 mg组及氯吡格雷组。在基线、负荷量服药后6~8 h、随机后7~10 d及随机后第28天分别采用VerifyNow测定P2Y12反应单位(PRU),并计算血小板聚集抑制百分比(%IPA)。主要研究终点为第28天的%IPA。在北部战区总医院入选的患者中,每组选取8~12例作为预设的亚组进行药代动力学检测,测量参数包括最大血浆浓度时间点(T_(max))、最大血浆浓度(C_(max))及血药浓度-时间曲线下面积(AUC)。结果最终入选201例患者,年龄(58.8±8.5)岁,其中男性139例(69.2%)。非LOF携带患者中,维卡格雷5、6、7.5 mg组与氯吡格雷组在各检测点的PRU和%IPA值的差异均无统计学意义(P均>0.05)。LOF携带患者中,负荷量服药后6~8 h维卡格雷5、6、7.5 mg组与氯吡格雷组的%IPA差异有统计学意义[22.9(14.2,31.5)%比19.8(11.0,28.6)%比29.5(20.9,38.0)%比12.9(3.9,21.9)%,P=0.038],随机后7~10 d 4组的%IPA差异亦有统计学意义[22.4(14.2,30.5)%比34.4(26.1,42.6)%比39.8(31.8,47.9)%比24.7(16.3,33.2)%,P=0.001],随机后第28天维卡格雷各治疗组的%IPA有高于氯吡格雷组的趋势[30.4(21.3,39.6)%比36.5(27.2,45.7)%比40.8(31.8,49.8)%比30.7(21.2,40.2)%,P=0.056]。共35例患者接受了药代动力学检测,结果显示,在非LOF携带者中,不同剂量维卡格雷组与氯吡格雷组的代谢产物M15-2的C_(max)值和AUC差异均无统计学意义(P均>0.05);而在LOF携带者中,维卡格雷5、6、7.5 mg组与氯吡格雷组的AUC差异�Objective To compare the antiplatelet effects of vicagrel and clopidogrel in patients with different cytochrome P450(CYP)2C19 genotypes.Methods This is a post-hoc analysis of a phaseⅡclinical trial of vicagrel,which included patients with coronary heart disease who underwent percutaneous coronary intervention from August 2018 to June 2019 in 18 centers.Patients were categorized based on the presence of CYP 2C19*2 or*3 loss-of-function(LOF)alleles into LOF carrier group(n=111)and non-LOF carrier group(n=90).Each group included patients received vicagrel 5 mg,6 mg,7.5 mg,or clopidogrel 75 mg for 28 days per study protocol.P2Y12 reaction units(PRU)were measured using VerifyNow at baseline,6 to 8 hours after loading dose,7 to 10 days after randomization,and 28 days after randomization and the percentage inhibition of platelet aggregation(%IPA)was calculated.The primary endpoint was%IPA on day 28.Within the patients from the General Hospital of Northern Theater Command,8 to 12 patients in each study arms were enrolled in a prespecified pharmacokinetic sub-study,measuring the time to reach maximum plasma concentration(T_(max)),peak plasma concentration(C_(max)),and area under the plasma concentration-time curve(AUC).Results Among 201 patients,the age was(58.8±8.5)years,and 139(69.2%)were male.In non-LOF carriers,there was no significant differences in PRU values and%IPA between the vicagrel 5 mg,6 mg,7 mg,and clopidogrel groups at all time points(all P>0.05).In LOF carriers,%IPA was significantly higher in the vicagrel-treated groups than in the clopidogrel group at 6-8 hours after loading dose(22.9(14.2,31.5)%vs.19.8(11.0,28.6)%vs.29.5(20.9,38.0)%vs.12.9(3.9,21.9)%,P=0.038)and 7-10 days after randomization(22.4(14.2,30.5)%vs.34.4(26.1,42.6)%vs.39.8(31.8,47.9)%vs.24.7(16.3,33.2)%,P=0.001),with a trend towards higher%IPA in the vicagrel-treated groups at day 28(30.4(21.3,39.6)%vs.36.5(27.2,45.7)%vs.40.8(31.8,49.8)%vs.30.7(21.2,40.2)%,P=0.056).Pharmacokinetic results of 35 patients showed that the C_(max) and AUC of t

关 键 词：冠心病 经皮冠状动脉介入治疗 血小板功能 药物基因组学 氯吡格雷 维卡格雷 

分 类 号：R541.4[医药卫生—心血管疾病]