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1、藉药物基因学检测决定华法令的用药剂量 Warfarin Pharmacogenomics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2Anti-coagulantslWafarinlHeparinlLMWHlFondaparinuxlBivalirudinlRivaroxabanlAntithrombinIIIlProteinClProteinSlTissuefactorpathwayinhibitor凝血因子、维他命K和华法令l肝细胞制造凝血因子、l凝血因子、蛋白质炼上的麸氨酸须经r-carboxylation。必须维他命K。维他命K华法令华法令的临床用途 静脉血栓肺栓塞房颤
2、瓣膜置换术Warfarin临床使用华法令l急诊最常见的药害: 1.胰岛素 2.华法令l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。l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 药效学(PD)和药物动力学(PK)lDrug metabolizing enzymes (DME): Prodrugs = active drugs (Codeine/Morphine)Active drugs = inactive compounds (warfarin)lDrug transportersInfluence intracellular drug concen
3、trations; much less well-studied药物动力学(PK)药物分解代谢酵素lPhase I: Oxidation, reduction, hydrolysislPhase II: Attach other chemical entities: acetylation, glucuronidation, sulfation, methylationPharmacogenomics: Translating Functional Genomics into Rational Therapeutics. Evans and Relling Science 1999华法令相关的
4、29类基因VKOR基因& CYP2C9基因lVitamin K epoxide reductase complex , subunit 1 (VKOR) lCytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9)II,VII,IX,XII,VII,IX,Xl Sickle cell anemiaCAG CTG (Glu Val)l Polymorphism: allele 1%基因突变与多形性基因突变与多形性对偶基因基因型CYP2C9 & VKOR对偶基因 VKOR对偶基因: -1639 G或-1639A CYP2C9对偶基因
5、: CYP2C9*1(wild ), CYP2C9*2, CYP2C9*3CYP2C9VKORII,VII,IX,XII,VII,IX,X华法令用量:东西方人不同EthnicityWarfarin doseReferencesAsian Chinese3.3 (mg/day)Q. J. Med. 89,127-135Japanese3.3 (mg/day)Clin. Pharmacol. Ther. 63, 519-528CaucasianAmerican5.1 (mg/day)JAMA, 287, 1690-1698.Italian5.5 (mg/day)Blood, 105, 645-64
6、9.“Geneticspoints“Geneticspointsthegunbutthegunbutenviromentenviromentpullspullsthetrigger!”thetrigger!”VKORC1 & CYP2C9对偶基因的差异VKORC1 (-1639) CYP2C9 G A*1 *2 *3 9% 91%95%0%5% 63% 37%70%20%10%中国人西方人 VKORC1 & CYP2C9基因型东西方差异VKORC1基因型与华法令用量aP value of comparison between AA and AG+GG groups.P-valueG aboli
7、sh the Ebox CAGGTG (E-box)CGGGTG (E-box abolished)Clin Pharmacol Ther 2008 Jul;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108病人 VKORC1和CYP2C9快速定型VKORC1 -1639 GAGGGGGGAGAGAGAAAAAACYP2C9*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3*1/*1*1/*3*3/*3Starting Dose (mg)53.753.753.752.52.52.51.251.25PT INR (2-3);华法令调剂量 1周2周4
8、周、8周、12周、6月随访PT INR (2-3);华法令调剂量 PT INR (2-3);华法令调剂量前瞻性试验Clin Pharmacol Ther 2008 Jul;84(1):83-9. 1周1周1周VKORC1-1639GACYP2C9StartingDose(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 (7
9、6.9%)58(69.9%)AA*1/*31.254 (3.7%)2(50%)AA*3/*31.2500Total n(%)108(100%)74(68.5%)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l83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%。l治疗第12周，华法令的平均剂量2.760.88 mg (16 mg)。 。74/108 (69%)预测值与实际值吻合l基因检测对于低(1 mg)或高剂量(5 mg)组特别有帮助基因检测对低或高剂量华法令组有帮助NEJM 2009;360:753-64回归分析Dose=-0.432+0.76
10、9xpredictdose-0.015xAge+1.125xBSADosealgorithm:Thesefactorsinthismodelaccountedfor48%.R2=0.482 WarfarinSensitivityTestCYP2C9:PolymorphismsproducedefectiveCYP2C9proteinthatreducemetabolismofwarfarin,thusmoresensitivetowarfarinVKORC1(vitaminKepoxidereductasecomplexsubunit1):warfarininhibitsVKORC1,andh
11、aplotypesassociatedwithchangeinactivityandwarfarindoseVerigene(NanosphereInc.)FDAClearsGeneticLabTestforWarfarinSensitivityTheU.S.FoodandDrugAdministrationtodayclearedformarketinganewgenetictestthatwillhelpphysiciansassesswhetherapatientmaybeespeciallysensitivetotheblood-thinningdrugwarfarin(Coumadi
12、n),whichisusedtopreventpotentiallyfatalclotsinbloodvessels.One-thirdofpatientsreceivingwarfarinmetabolizeitquitedifferentlythanexpectedandexperienceahigherriskofbleeding.Researchhasshownthatsomeoftheunexpectedresponsetowarfarindependsonvariantsoftwogenes,CYP2C9andVKORC1.TheNanosphereVerigeneWarfarin
13、MetabolismNucleicAcidTestdetectssomevariantsofbothgenes.TodaysactionoffersphysiciansthefirstFDAclearedgenetictestforwarfarinsensitivity,whichisanotherstepinourcommitmenttopersonalizedmedicine,”saidDanielSchultz,M.D.,director,FDAsCenterforDevicesandRadiologicalHealth.“Withthistest,physiciansmaybeable
14、tousegeneticinformationalongwithotherclinicalinformationtotreattheirpatients.”Warfarinisthesecondmostcommondrug,afterinsulin,implicatedinemergencyroomvisitsforadversedrugevents.FORIMMEDIATERELEASEFORIMMEDIATERELEASESeptember17,2007September17,2007个人化医学If it were not for the great variability amongIn
15、dividuals, medicine might as well be a science and not an art.- Sir William Osler, 1892 结论l华法令的有效且安全的范围很窄，须反复检测血液的INR，以达到最终适合的治疗剂量l华法令在体内的药理作用深受VKORC1和CYP2C9两种酵素的影响lVKORC1-1639 G或A的多形性，影响VKORC1酵素的生成量。-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lCYP2C9基因存在CYP2C91、CYP2C92、CYP2C93三型。CYP2C91代谢华法令的功能正常。但CYP2C92和CYP2C93的代谢分解华法令的能力降低。l使用华法令药物前，若能先作血液基因检测，以决定华法令初始用药剂量，将可大幅缩短调整华法令剂量所须的时间，也可避免华法令用药过量或不足引起的副作用 Slide 33荣民总医院日月潭阿里山云海Slide 34
