CYP2C19-基因检测对药物的个体化指导.ppt

October, 2006 Hulot et al identify CYP2C19 polymorphisms as major determinant of variability in platelet aggregation in healthy subjects; additional publications later confirm this finding 2006 2007 2008 May, 2008 Trenk et al find CYP2C19 polymorphism is associated with adverse outcomes for patients on clopidogrel followed for one year 2009 December, 2008 Three additional outcome studies, including TRITON-TIMI 38, demonstrate a higher risk of CV events for CYP2C19 poor metabolizers on clopidogrel May, 2009 FDA revises clopidogrel label to include descriptive Information about individuals with genetically reduced CYP2C19 activity Emerging information established a role for CYP2C19 in clopidogrel response Oct, 2009 Press Release: Quest Diagnostics Brings Genetic Testing for Plavix(R) Response to Coronary Stent Patients at Scripps Health; First saliva-based cardiovascular disease test from Quest Diagnostics identifies gene variants implicated in potentially lethal reaction to popular anti-clotting drug 2010 October, 2009 Press Release: MEDCO announces the “Genotype-Guided Comparison of Clopidogrel and Prasugrel Outcomes Study” to enroll 14,000 patients with ACS * Mega Study 基因型确定：在162健康人中寻找P450功能性突变（活性药物代谢浓度、血小板抑制反应） 方法：主要基因芯片(Affymetrix) 人群：1477人，随访1.5年 检测基因 CYP2C19功能性突变，与预后有意义 CYP2C9功能性突变，但与预后无意义 CYP2B6非功能性 CYP3A5非功能性 CYP1A2非功能性 Cytochrome P-450 Polymorphisms and Response to Clopidogrel * ADP受体 (P2RY12, ITGB3) ABCB1调控 药物吸收分布 肝脏细胞色素P450代谢酶 (CYP3A4, CYP3A5, CYP2C19) Taken from Simon et al. NEJM 2009; 360: 363-75 氯吡格雷在人体中的代谢过程 心血管事件率 ? CYP 2C19 氯吡格雷活性代谢产物生成减少 血小板聚集率 ? 研究数据表明：在接受氯吡咯雷治疗的人群中，CYP2C19基因突变者支架血栓形成和死亡风险均显著高于非突变患者。 主要终点事件 血栓再发率 法国：2208个急性心梗患者 对于因为急性心梗而服用氯吡格雷的病人，那些携带CYP2C19基因突变（*2、*3、*4、*5）的患者比非携带者有更高的心血管不良事件发生的风险。这种风险在做冠脉支架术的病人中更为显著。 CYP2C19(*2, *3, *4, or *5)携带其中任何二个等位基因个体，比非携带者风险增加3.58倍 * Is it a key role for CYP2C19 in clopidogrel response？ * 2010年3月，美国FDA建议患者服用波立维前需检测CYP2C19基因型 波立维依赖于P450酶系主要CYP2C19代谢生成活性代谢产物来发挥抗血小板疗效。 弱代谢型的ACS或接受PCI治疗的患者，在接受推荐剂量波立