医疗机构开展基因导向个体化给药的机遇和瓶颈-胡永芳

医疗机构开展基因导向个体化给药的机遇和瓶颈北京大学三医院胡永芳副教授研究基础(循证证据）临床应用的瓶颈政策方面管理规定收费标准OutlineforReportInwhatwayscandoctorsusepharmacogeneticstohelpthemtreattheirpatients?TherightdoseTherightdrugforcancerforHIVfordepressionforcardiovasculardisease基因型为HLA-B*1502型患者更容易发生白种人群SJS/TEN发生率仅有0.1‰~0.6‰，有些亚洲国家SJS/TEN的发生率大约要高出10倍(1%~0.6%)HLA-B*1502的突变等位基因发生率中国、泰国、马来西亚、印度尼西亚、菲律宾和台湾部分地区为10~15%南亚人（包括印度人）为2-4%日本和韩国的发生率1%HLA-B*1502突变等位基因发生频率2%，需监测基因型突变型纯合子（阳性），则不宜使用卡马西平HLA-B*1502阳性者用其他诱发SJS/TEN药品发生风险增加基因监测避免严重不良反应卡马西平与SJS基因监测选择最佳药物吉非替尼与EGFR应答率EGFR突变阳性者(132)71.2%vsEGFR突变阴性者(91)1.1%HowdoIgetapharmacogenetictest?MayoClinic,theIndianaUniversitySchoolofMedicineSt.JudeChildren'sHospitalCostAfewhundreddollarsMaybecoveredbyyourhealthinsurancecompany“ClopidogrelshouldbeusedinhospitalizedpatientswhocannottakeaspirinbecauseofmajorGIintolerance.”(ClassIArecommendation)BraunwaldE,etal.JAmCollCardiol2002AHA-ACCPracticeGuidelinesClinicalimpactofadruginteractionbetweenclopidogrelandPPIJAmCollCardiol2008;52:1038-9CYP2C19DeficiencyandStentThrombosisPooledBaselineCharacteristicsbyCYP2C19GenotypeStatusCardiovascularDeathbyCYP2C19genotypeCardiovascularDeathbyCYP2C19genotypeMyocardialInfarctionbyCYP2C19genotypeIschemicStrokebyCYP2C19genotypeTimingofEventsforCardiovascularDeath,MyocardialInfarction,orIschemicStrokeandStentThrombosis如何确定剂量或换用其他药物——瓶颈弱代谢300mg?600mg?普拉格雷？ARCTIC-GENE(AssessmentWithaDoubleRandomizationofaMonitoringadjustedAntiplateletTreatmentVersusaCommonAntiplateletTreatmentforDESImplantationandInterruptionVersusContinuationofDoubleAntiplateletTherapy,OneYearAfterStenting)study常用、唯一的口服抗凝药物适应证心脏瓣膜置换（INR：2.5-3.5）深静脉血栓（INR：2-3）肺栓塞（INR：2-3）房颤（INR：2-3）抗凝过度—Bleeding（2~10%）抗凝不足—Thrombosis（0.5~2‰）反复调试，延长住院天数华法林个体化给药WoodcockJ,etal.,NEnglJMed2009:360(8);811-3.基因监测拟定给药剂量Schwarzetal.(2008)NEnglJMed352:999-1007.EffectofcombinedCYP2C9/VKORC1genotypeonwarfarindoseWarfarinDose(mg)CYP2C9GenotypeVKORC1Genotype*2*3/*3*3(n=11)*2*2(n=8)*1*3n=42)*1*2(n=66)*1*1(n=163)GGGAAAGGGAAAGGGAAAGGGAAAGGGAAA1210864201.001.921.062.502.022.933.031.644.283.502.685.204.362.41Sconceetal.(2005)Blood106:2329-33EffectofcombinedCYP2C9/VKORC1genotypeonwarfarindoseGenetictests!!基因监测拟定给药剂量EffectofcombinedCYP2C9/VKORC1genotypeandsex/ageonwarfarindoseWadeliusetal.(2009)Blood113:784-7920.85mg(0.60–1.11mg),17%reductionSandersonSetal.,GenetMed2005:7(2):97–104.Meandailydosereduction2C9*29studies,2775patients,CaucasiansSandersonSetal.,GenetMed2005:7(2):97–104.1.92mg(1.37–2.47mg),37%reductionMeandailydosereduction2C9*3SandersonSetal.,GenetMed2005:7(2):97–104.1.71mg(1.22–2.20mg),27%reductionMeandailydosereduction2C9*2and*3Meandailydosereduction2C9*2and*3张婷,胡永芳.中国临床药理学2009EffectofcombinedCYP2C9/VKORC1genotypeandsex/ageonwarfarindoseWadeliusetal.(2009)Blood113:784-792CYP2C9VKORC1,VitaminKepoxidereductaseOthercandidategenes(GGCX,APOE)EffectofcombiningCYP2C9andVKORC1Non-geneticfactors(age,gender)Warfarin&PharmacogeneticsvariablevalueGenderfemale-n(%)80(58%)Age-years69±12Indicationfortreatment-n(%)Atrialfibrillationofflutter61(41.5%)Thrombosisorembolus33(22.5%)Pulmonaryembolism28(19.1%)valvereplacement16(10.9%)others9(6.1%)TargetofINR2.0-3.0123(88%)2.5-3.516(12%)RetrospectiveStudyincollaborationwithPekingUniversityThirdHospital(n=139)DemographiccharacteristicGene/SNPNallele(%)genotype(%)WMW/WW/MM/MVKORC1rs99232311820.920.080.8460.1480.005rs99344381820.9070.0930.8520.1760.005rs72941820.9230.0770.8520.1430.005CYP2C9rs17998531810.9970.0030.9940.0060rs10579101820.9620.0380.9230.0770GGCXrs69966441820.6480.3520.4120.4730.115APOErs4293581800.9170.0830.8390.1560.006rs74121790.9330.0670.8720.1230.006ThefrequenciesofallelicandgenotypeinVKORC1,CYP2C9,GGCX,APOEGene/dilotypeNnFrequencie(%)CYP2C9181CC-AA1660.917CC-AC140.077TC-AA10.006VKORC1182AA-TT-AA1490.819AA-CT-AA50.027AG-CT-AA10.005AG-CT-GA260.143GG-CC-GG10.005APOE179TT-CC1300.726TT-CT190.106TC-TT10.006TC-TC30.017TC-CC230.128CC-CC10.006ThefrequenciesofdilotypeinVKORC1,CYP2C9andAPOEWarfarinmeandaliydosePvalueW/WW/M+M/MVKORC1rs99232312.23±0.963.59±1.07＜0.0001rs99344382.69±0.923.56±1.01＜0.0001rs72942.72±0.913.56±1.06＜0.0001CYP2C9rs10579102.84±1.022.89±0.770.703APOErs4293583.87±1.032.70±0.880.789rs74122.79±0.973.00±0.850.435AassociationbetweenpolygeneticSNPsandwarfarindose(1)AassociationbetweenpolygeneticSNPsandwarfarindose(2)WarfarinmeandaliydosePvalueW/WW/MM/MGGCXrs69966444.15±1.072.83±0.872.74±1.110.436ArelationshipbetweenwarfarinmeandailydosewithVKORC1dilotype基因监测拟定给药剂量PharmacogeneticAlgorithmVSFixed-DoseApproachTheInternationalWarfarinPharmacogeneticsConsortium.(2009)NEnglJMed352:753-764.每年避免85,000严重出血件17,000例中风发生减少医疗花费11亿美元样本编号20110304住院号288978姓名张文表科别急诊科床位号无性别男临床诊断年龄76岁华法林敏感性+低-中-中-高-高-高+低-中-高+低-中-高报告日期2011-3-8检验人唐惠林报告人毛玉丹/胡永芳北京市海淀区花园北路49号邮编100191联系电话：[phone]CYP2C9*1/*1CYP2C9*1/*2VKORC1-1693GAVKORC1-1693GGCYP2C9*1/*3CYP2C9*2/*2CYP2C9*3/*33、密切随访患者，定期检测INR值。北京大学第三医院CYP2C9*2/*3VKORC1-1693AA华法林敏感性基因型检测报告芯片图华法林敏感性基因检测结果基因位点检测结果4、注意华法林与其它药物的相互作用。呼吸困难待查，心功能不全，冠心病，高血压，糖尿病北京大学第三医院VKORC11173TTVKORC11173CTVKORC11173CC临床药师建议2、依据患者基因型和患者的年龄、体重等因素综