多组学研究与个体化用药

2017/5/231药学院多组学研究与个体化用药黄民中山大学临床药理研究所中山大学药学院药物代谢与药动学实验室2017.5.20长沙1传统用药方式2“千人一面”“大众医疗”药物反应个体差异-表现3有效性药物不良反应严重•全球死亡主要原因第4-6位•医院费用5%-9%与药物不良反应有关•中国：因药物不良反应住院人数:250万/年，严重不良反应人数:50万/年，因药物不良反应死亡人数:20万/年安全性药物效应个体差异-原因4生理因素病理因素遗传因素环境因素合并症、器官功能、病程等食物、吸烟、药物相互作用等身高、体重、性别、年龄等遗传药理学药物基因组2017/5/232批准药品说明书中的遗传变异-1生物标记检测药物或代表药1CC趋化因子受体5(CCR-5)1马拉维若(抗逆转录病毒药)2EGFR表达等1Panitumab（EGFR单抗）、吉非替尼（大肠癌）3Her2/neu过表达1西妥昔单抗4费城染色体阳性反应等1达沙替尼5C蛋白缺损(遗传性或获得性）2华法林6TPMT变异2硫唑嘌呤7UGT1A1变异2伊立替康8HLA-B*1502等位基因2*卡马西平9尿素循环障碍(UCD)2丙戊酸10CYP2C9突变等2华法林11VitK环氧化还原酶(VKORC1)变异2华法林12家族性高脂蛋白血症LDL受体缺损或突变2阿托伐他汀13G6PD缺损2拉布立酶14HLA-B*5701等位基因2阿巴卡韦1.要求检测2.推荐检测3.有报告2*在危险人群中检测7生物标记检测药物或代表药15C-KIT表达3伊马替尼甲磺酸16PML/RAR()表达(维甲酸受体反应/无反应)3维甲酸17UGT1A1变异等3尼罗替尼18CYP2C19突变3伏立康唑19CYP2C9突变3塞来昔布20CYP2D6变异3托莫西汀21CYP2D6和其他变异3盐酸氟西汀22第五对染色体长臂间隙基因缺损3来那度胺23DPD缺损3卡培他滨24EGFR表达3埃罗替尼25EGFR表达等3吉非替尼（头颈癌）26G6PD缺损等3伯氨喹27NAT变异3异烟肼，马利兰28费城染色体阳性反应者3马利兰1.要求检测2.推荐检测3.有报告2*在危险人群中检测FDA批准药品说明书中的遗传变异-2基因组研究DNA序列个体差异，仍不能完全解释药物反应个体差异的现象，比如，DNA序列相同的情况下仍具有不同表型的现象则无法解释。需要进一步结合表观遗传学、转录组学、蛋白质组学、内环境（代谢组学、肠道微生物组学）等进行研究。药物基因组学的局限性多组学研究82017/5/233。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。。贯穿组学(Trans-omic)研究精准构建调控网络，发现功能性生物标志物及靶标存在选择偏倚发现强关联性标志物，但难于发现功能性生物标志物精准构建调控网络，发现功能性生物标志物，作为潜在干预靶标Science.2016CellSyst.201791.CyclosporineA(CsA)2.Warfarin3.Valproicacid(VPA)4.Cyclophosphamide(CPA)5.Thiopurines(AZA&6-MP)我们的工作106.Tacrolimus(FK506)7.Lamotrigine(LTG)8.Gefitinib1.CyclosporineA(CsA)11First-lineimmunosuppressantTherapeuticwindow:NarrowNoconsistentresultinCYP3A4/5&MDR1geneticpolymorphismsPharmacokinetics:HighlyvariableTDM:RetardationCyclosporineA(CsA)CyclosporineA122017/5/234OurrecentfindingsZhangY,HuangM*.ActaPharmacolSin.2013GeneticpolymorphismsofNF-kappaBpathwayrelatedcouldsignificantlyinfluenceCsAconcentrations.13PredictionmodelThepredictionmodelcouldexplain41.2%oftheinter-individualvariationofcyclosporineconcentrations.CsAC0/D=53.977+16.774*RELArs7119750TT+12.700*NFKBIA2758AA+28.871*TNFAIP3rs2230926GT-21.048*PORrs17685TT+13.663*RELArs11820062CC+17.513*MDR11236TT-2677TT-3435TT142.Warfarin15•First-lineanticoagulant•Therapeuticwindow:Narrow•InternationalNormalizedRatio(INR)monitoringWarfarinRetardation•Highlyvariabledosagerequirement•ADR:Fatalbleedingorthromboembolism162017/5/235WarfarinPD/PKpathwaysIn2007,theFDAmodifiedthewarfarinlabel,statingthatCYP2C9andVKORC1genotypesmaybeusefulindeterminingtheoptimalinitialdoseofwarfarin.Dose=antilog(0.51986-0.31765×VKORC13673AA-0.13784×VKORC13673AG+0.20994×*1*1-0.0772×CYP4F2CC-0.04010×CYP4F2CT+0.08570×BSA-0.21551×Cordarone-0.00116×age)Generalr2ofthemodel=56.1%,thepercentageofinter-individualvariabilityofstablewarfarindosebythismodel.CenHJ,HuangM*.BritJClinPharmacol.2010173.Valproicacid(VPA)18VPA-inducedobesity54kg65kg69kg64kg88kg76kg（1month）（threemonth）（sixmonth）Valproicacid(VPA)VPAconc：65.72μg/mLVPAconc：52.51μg/mLVPAconc：29.87μg/mLItwasconsideredthatVPA-inducedobesitywascloselycorrelatedwithVPAconcentration,butourclinicobservationshowedthattheobesityseemstobepoorcorrelationwithVPAconcentration.1919HepatotoxicityiscorrelatedwithVPACss,howeverthereisnocorrelationbetweenthedegreeofweightgainandtheVPAconcentration.VPACssandVPA-inducedweightgainandhepatotoxicity20LiHL,HuangM*.IntJNeuropsychopharmacol.2015ab202017/5/236SNPsinLEPR,ANKK1,PRKAA2correlatedwithVPA-inducedobesityAA:1.71±1.49kg/m2,n=4AG:1.19±1.18kg/m2,n=46GG:0.6±1.17kg/m2,n=162CC:1.01±1.37kg/m2,n=73CT:0.76±1.22kg/m2,n=91TT:0.35±0.69kg/m2,n=48AA:0.69±1.27kg/m2,n=150AG:0.87±0.99kg/m2,n=54GG:1.23±1.08kg/m2,n=8LEPRPRKAA2ANKK21LiHL,HuangM*.IntJNeuropsychopharmacol.2015214.Cyclophosphamide(CPA)22CYP2B6,3A4,2C19,2C9NonenzymaticCyclophosphamide(CPA)4-OHCPAGSTsGSTsEliminationEliminationCyclophosphamide(CPA)CPAisthefirstlinedrugusedinsystemiclupuserythematosus(SLE)patients2324P0.001CYP2C19*24-HydorxycyclophosphamideC20h(ng/mL)P0.0014-HydorxycyclophosphamideC20h(ng/mL)CYP2B6-750CT4-HydorxycyclophosphamideC20h(ng/mL)CopyNumberofCYP2B6P=0.001P=0.002CYP2C19andCYP2B6geneticpolymorphismsweresignificantlyassociatedwith4-hydroxyCPAconcentration(CPAactivemetabolite).ShuWY,HuangM*.BrJClinPharmacol.2016CYP2C19,CYP2D6andCPA242017/5/237VariableBeta-standardizedcoefficientspvaluePartialrPartialr2CYP2C19*2-0.3970.001-0.4640.215CYP2B6-750CT0.3790.0010.4550.207CYP2B6-2320CT-0.1850.001-0.2480.059CopyNumberofCYP2B60.2220.0020.2730.075CYP2B6C15582T-0.1590.017-0.2110.044PXRrs13059232-0.1430.028-0.2040.037Themodelexplain48.4%ofinter-individualvariabilityof4-OHCPA(basedonage,genderandgenotypes).CYP2C19*2,CYP2B6-750CTarethemostimportantfactors.Theprevalenceofthesetwoclinicallyrelevantgenotypes(CYP2C19*2andCYP2B6-750CtoT)weresimilartootherethnicpopulations.Predictionmodel25PatternofCPAmetabolism265.Thiopurines(AZA&6-MP)2728GSTXOHPRTTPMTIMPDHGMPSITPA6MMPR6TGN6MeTITP6MeTIDP6MeTIMPdenovoPurinesynthesisTGDPTGTPTdTGDPTdTGTPIncoporationintoRNAorDNARac1AZA6MPTIMPTXMPTGMPTITP6TUCytotocixityNDUT15Thiopurines(AZA&6-MP)DingL,HuangM*.InflammBowelDis.2012;18(1):