药物基因学及临床应用课件

藉药物基因学检测决定华法令的用药剂量

WarfarinPharmacogenomics常敏之医师荣民总医院心脏科阳明大学心脏血管研究中心榮民總醫院藉药物基因学检测常敏之医师榮民總醫院Anti-coagulantsWafarinHeparinLMWHFondaparinuxBivalirudinRivaroxaban

AntithrombinIIIProteinCProteinSTissuefactorpathwayinhibitorAnti-coagulantsAntithrombinI凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ、维他命K和华法令肝细胞制造凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ蛋白质炼上的麸氨酸须经r-carboxylation。必须维他命K。维他命K华法令凝血因子Ⅱ、Ⅶ、Ⅸ、Ⅹ、维他命K和华法令肝细胞制造凝血因子Ⅱ华法令的临床用途

静脉血栓肺栓塞房颤瓣膜置换术Warfarin华法令的临床用途肺栓塞房颤Warfarin临床使用华法令急诊最常见的药害:1.胰岛素2.华法令华法令的有效且安全的范围很窄，且个体所须剂量的差异极大。须藉一连串检测血液的凝血酵素原时间（INR），才足以调整达到最终的治疗剂量

临床使用华法令急诊最常见的药害:1.胰岛素2.华法令药效学(PD)和药物动力学(PK)药效学(PD)和药物动力学(PK)Drugmetabolizingenzymes(DME):Prodrugs=>activedrugs(Codeine/Morphine)Activedrugs=>inactivecompounds(warfarin)DrugtransportersInfluenceintracellulardrugconcentrations;muchlesswell-studied药物动力学(PK)Drugmetabolizingenzymes(DME药物分解代谢酵素PhaseI:Oxidation,reduction,hydrolysisPhaseII:Attachotherchemicalentities:acetylation,glucuronidation,sulfation,methylationPharmacogenomics:TranslatingFunctionalGenomicsintoRationalTherapeutics.EvansandRellingScience1999药物分解代谢酵素PhaseI:Pharmacogenom华法令相关的29类基因华法令相关的29类基因VKOR基因&CYP2C9基因VitaminKepoxidereductasecomplex,subunit1(VKOR)CytochromeP450,family2,subfamilyC,polypeptide9(CYP2C9)II,VII,IX,XII,VII,IX,XVKOR基因&CYP2C9基因VitaminKepoxSicklecellanemiaCAG→CTG(Glu→Val)Polymorphism:allele>1%

基因突变与多形性Sicklecellanemia

基因突变与多形性基因突变与多形性药物基因学及临床应用课件对偶基因

基因型对偶基因基因型CYP2C9

&VKOR对偶基因VKOR对偶基因:-1639G或-1639ACYP2C9对偶基因:CYP2C9*1(wild),CYP2C9*2,CYP2C9*3CYP2C9VKORII,VII,IX,XII,VII,IX,XCYP2C9&VKOR对偶基因VKOR对偶基因:-1华法令用量:东西方人不同EthnicityWarfarindoseReferencesAsian

Chinese3.3(mg/day)Q.J.Med.89,127-135Japanese3.3(mg/day)Clin.Pharmacol.Ther.63,519-528Caucasian

American5.1(mg/day)JAMA,287,1690-1698.Italian5.5(mg/day)Blood,105,645-649.华法令用量:东西方人不同EthnicityWarfarin“Geneticspointsthegunbutenviromentpullsthetrigger!”“GeneticspointsthegunbuteVKORC1&CYP2C9对偶基因的差异VKORC1(-1639) CYP2C9G A *1 *2 *39% 91% 95% 0% 5%63% 37% 70% 20% 10%中国人西方人VKORC1&CYP2C9对偶基因的差异VKORC1(

VKORC1&CYP2C9基因型东西方差异VKORC1&CYP2C9基因型东西方差异VKORC1基因型与华法令用量aPvalueofcomparisonbetweenAAandAG+GGgroups.P-value<0.0001usingTtest.Datarepresentmean±SD.VKORC1起动子-1639位点出现G或A的多型性。-1639AA基因型所需华法令的维持剂量远低于-1639AG或-1639GG基因型所需的剂量。VKORC1基因型与华法令用量aPvalueofcomVKORC1启动子活性:G,A不同VKORC1-1639AhaslessVKORC1promoteractivityandlessVKORC1E-boxconsensus:CANNTGHypothesis:-1639A>GabolishtheEboxCAGGTG(E-box)CGGGTG(E-boxabolished)VKORC1启动子活性:G,A不同VKORC1-1639ClinPharmacolTher2008Jul;84(1):83-9.荣总、台大、长庚、高医大、新光医院中央研究院生物医学研究所ClinPharmacolTher2008Jul;8108病人VKORC1和CYP2C9快速定型VKORC1-1639G>AGGGGGGAGAGAGAAAAAACYP2C9*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3StartingDose(mg)53.753.753.752.52.52.51.251.25PTINR(2-3);华法令调剂量

1周2周4周、8周、12周、6月随访PTINR(2-3);华法令调剂量

PTINR(2-3);华法令调剂量前瞻性试验ClinPharmacolTher2008Jul;84(1):83-9.1周1周1周108病人VKORC1和CYP2C9快速定型VKORC1VKORC1-1639G>ACYP2C9StartingDose(mg/d)Frequencyn(%)DoseMatchn(%)GG*1/*153(2.8%)2(66.7%)GG*1/*33.7500GG*3/*33.7500AG*1/*13.7517(15.7%)12(70.5%)AG*1/*32.51(0.9%)1(100%)AG*3/*32.500AA*1/*12.583(76.9%)58(69.9%)AA*1/*31.254(3.7%)2(50%)AA*3/*31.2500Totaln(%)108(100%)74(68.5%)第12周随访华法令的用量分析VKORC1CYP2C9StartingDoseFre第12周随访华法令的用量分析第12周随访华法令的用量分析结果83％的病患在华法令治疗2周内就可达到血中稳定的治疗INR值。在治疗第4周可达到90%。治疗第12周，华法令的平均剂量2.760.88mg(1~6mg)。。74/108(69%)预测值与实际值吻合基因检测对于低(1mg)或高剂量(5mg)组特别有帮助结果83％的病患在华法令治疗2周内就可达到血中稳定的治疗IN基因检测对低或高剂量华法令组有帮助NEJM2009;360:753-64基因检测对低或高剂量华法令组有帮助NEJM2009;360回归分析Dose=-0.432+0.769xpredictdose-0.015xAge+1.125xBSADosealgorithm:Thesefactorsinthismodelaccountedfor48%.R2=0.482

回归分析Dose=-0.432+0.769xpWarfarinSensitivityTestCYP2C9:PolymorphismsproducedefectiveCYP2C9proteinthatreducemetabolismofwarfarin,thusmoresensitivetowarfarinVKORC1(vitamin

Kepoxidereductasecomplexsubunit

1):warfarininhibitsVKORC1,andhaplotypesassociatedwithchangeinactivityandwarfarindoseVerigene®(NanosphereInc.)WarfarinSensitivityTestCYP2CFDAClearsGeneticLabTestforWarfarinSensitivity

TheU.S.FoodandDrugAdministrationtodayclearedformarketinganewgenetictestthatwillhelpphysiciansassesswhetherapatientmaybeespeciallysensitivetotheblood-thinningdrugwarfarin(Coumadin),whichisusedtopreventpotentiallyfatalclotsinbloodvessels.One-thirdofpatientsreceivingwarfarinmetabolizeitquitedifferentlythanexpectedandexperienceahigherriskofbleeding.Researchhasshownthatsomeoftheunexpectedresponsetowarfarindependson

variantsoftwogenes,CYP2C9andVKORC1.TheNanosphereVerigeneWarfarinMetabolismNucleicAcidTestdetectssomevariantsofbothgenes."Today’sactionoffersphysicians

thefirstFDAclearedgenetictestforwarfarinsensitivity,whichisanotherstepinourcommitmenttopersonalizedmedicine,”saidDanielSchultz,M.D.,director,FDA’sCenterforDevicesandRadiologicalHealth.“Withthistest,physiciansmaybeabletousegeneticinformationalongwithotherclinicalinformationtotreattheirpatients.”Warfarinisthesecondmostcommondrug,afterinsulin,implicatedinemergencyroomvisitsforadversedrugevents.FORIMMEDIATERELEASE

September17,2007

FDAClearsGeneticLabTestfo药物基因学及临床应用课件个