個體化用藥高血壓治療的未來展望藥物基因組學(xué)

個體化用藥高血壓治療的未來展望藥物基因組學(xué)第1頁/共87頁ObjectivesProvideanoverviewofpharmacogenomicsanditsclinicalrelevanceDiscussclinically-relevantexamplesof:DrugmetabolismpharmacogenomicsDrugtargetpharmacogenomicsDiscussthechallengesfacingpharmacogenomicstudiesandthemovementofpharmacogenomicsintoclinicalpracticeDiscusspharmacogenomicsfromtheFDAandpharmaceuticalindustryperspective第2頁/共87頁InterindividualVariabilityinDrugResponseDisease

DrugClass

RateofPoorResponseAsthma Beta-agonists 40-75%Hypertension Various 30%SolidCancers Various 70%Depression SSRIs,tricyclics 20-40%Diabetes Sulfonylureas,others 50%Arthritis NSAIDs,COX-2inhibitors 30-60%Schizophrenia Various 25-75%第3頁/共87頁FactorsContributingtoInterindividualVariabilityinDrugDispositionandActionAgeRace/ethnicityWeightGenderConcomitantDiseasesConcomitantDrugsSocialfactorsGENETICSPERSONALIZEDMEDICINE第4頁/共87頁“Wewishtosuggestastructureforthesaltof[DNA].Thisstructurehasnovelfeatureswhichareofconsiderablebiologicalinterest.”第5頁/共87頁HumanGenomeProjectDeterminethesequenceofthe3billionnucleotidesthatmakeuphumanDNACharacterizevariabilityinthegenomeIdentifyallthegenesinhumanDNATheEraofGenomicMedicine:ImprovepredictionofdrugefficacyortoxicityImprovethediagnosisofdiseaseEarlierdetectionofgeneticpredispositiontodisease第6頁/共87頁NewsweekJune25,2001“…pharmacogeneticspromisestotargettreatmenttoapatient’sgeneticprofile…”第7頁/共87頁GeneticsorGenomics?PharmacogeneticsStudyofhowgeneticdifferencesinaSINGLEgeneinfluencevariabilityindrugresponse(i.e.,efficacyandtoxicity)PharmacogenomicsStudyofhowgenetic(genome)differencesinMULTIPLEgenesinfluencevariabilityindrugresponse(i.e.,efficacyandtoxicity)第8頁/共87頁CurrentConceptofPharmacogenomicsRodenDMetal.AnnInternMed2006;145:749-57第9頁/共87頁PotentialofPharmacogenomicsAllpatientswithsamediagnosis12Respondersandpatients

notpredisposedtotoxicityNon-respondersandtoxicrespondersTreatwithalternativedrugordoseTreatwith

conventionaldrugordose第10頁/共87頁ClinicalRelevanceCanwepredictwhowillderiveanoptimalresponse?Canwepredictwhowillhaveatoxicity?Host(patient)genotypedeterminesoptimaldrugtherapyapproachDisease(pathogen)genotypedeterminesoptimaldrugtherapyapproach第11頁/共87頁DNAisInformationDNAA,T,G,CCodonGeneChromosomeGenomeENGLISHAbcdefg….xyzWordSentenceChapterBook第12頁/共87頁CompositionoftheHumanGenomeMutation/Polymorphism 1bpUnitofgeneticcode 3bpCodingsequence(exons) 3,000bpGene(exonsandintrons) 50,000bpChromosome 150,000,000bpHumangenome 3,000,000,000bp第13頁/共87頁TheFoundationofPharmacogenomics:DifferencesintheGeneticCode

BetweenPeopleMutation:differenceintheDNAcodethatoccursinlessthan1%ofpopulationOftenassociatedwithrarediseasesCysticfibrosis,sicklecellanemia,Huntington’sdiseasePolymorphism:differenceintheDNAcodethatoccursinmorethan1%ofthepopulationAsinglepolymorphismislesslikelytobethemaincauseofadiseasePolymorphismsoftenhavenovisibleclinicalimpact第14頁/共87頁SingleNucleotidePolymorphisms(SNP)Pronounced“snip”SinglebasepairdifferenceintheDNAsequenceOver2millionSNPsinthehumangenomeOtherpolymorphisms:Insertion/deletionpolymorphismsGeneduplicationsGenedeletions第15頁/共87頁第16頁/共87頁ConsequencesofPolymorphismsMayresultinadifferentaminoacidorstopcodonMayresultinachangeinproteinfunctionorquantityMayalterstabilityofmRNANoconsequence第17頁/共87頁GeneticsTerminologyAlleles=differentDNAsequencesatalocusCodon3891-ARArg(0.75)Gly(0.25)Genotype=pairofallelesapersonhasataregionofthechromosome Codon3891-ARArg389ArgArg389GlyGly389Gly第18頁/共87頁GeneticsTerminologyPhenotype:outwardmanifestationofatraitLinkage:measureofproximityof2ormorepolymorphismsonasinglechromosomePolymorphismsincloseproximitytendtobeco-inheritedRegionsoflinkedpolymorphismsareknownashaplotypes第19頁/共87頁HaplotypeMapForspecificlocationsinthegenome,asmallnumberofSNPpatterns(haplotypes)canaccountfor80-90%ofentirehumanpopulationInternationalHapMapProject:IdentifyingcommonhaplotypesinfourpopulationsfromdifferentpartsoftheworldIdentifying“tag”SNPsthatuniquelyidentifythesehaplotypes第20頁/共87頁PharmacogenomicsDRUGTARGETSDRUGMETABOLIZINGENZYMESDRUGTRANSPORTERSPHARMACOKINETICSPHARMACODYNAMICSVariabilityinEfficacy/ToxicityJohnsonJA.TrendsinGenetics2003:660-666第21頁/共87頁DrugMetabolismPharmacogenomicsEvidenceofaninheritedbasisfordrugresponsedatesbackintheliteraturetothe1950sSuccinylcholine:1in3000patientsdevelopedprolongedmusclerelaxationMonogenicPhenotypetogenotypeapproach第22頁/共87頁DrugMetabolizingEnzymes第23頁/共87頁ExamplesofDrugMetabolismPharmacogenomicsNEJM2003;348:529-537第24頁/共87頁ExamplesofDrugMetabolismPharmacogenomics

NEJM2003;348:529-537第25頁/共87頁WarfarinandCYP2C9WidelyprescribedanticoagulantdrugusedtopreventbloodclotsNarrowrangebetweenefficacyandtoxicityLargevariabilityinthedoserequiredtoachievetherapeuticanticoagulationDosesvary10-foldbetweenpeopleCYP2C9istheenzymeresponsibleforthemetabolismofwarfarinSNPsexistinCYP2C9genethatdecreasetheactivityoftheCYP2C9metabolizingenzyme第26頁/共87頁CYP2C9PolymorphismsandWarfarinDoseWarfarindoseisaffectedbyCYP2C9genotypeGageBFetal.ThrombHaemost2004;91:87-94*2and*3areSNPs第27頁/共87頁CYP2C9GenotypeandBleedingEventsComparedtowild-type,CYP2C9variantshadahigherriskofseriousorlife-threateningbleedsHazardRatioof3.94duringthefirst3monthsoffollow-upHazardRatioof2.39fortheentirefollow-upperiod

Higashietal.JAMA2002;287WTVariant第28頁/共87頁ChallengesFacingWarfarinPharmacogenomicsDespitethestrongassociationbetweenCYP2C9genotypeandwarfarindose,CYP2C9genotypeaccountsforonlyasmallportionofthetotalvariabilityinwarfarindoses(~10-20%)Needtodetermineothergeneticandnon-geneticfactorsthatcontributetointerindividualvariabilityinwarfarindoses第29頁/共87頁CYP2D6PolymorphismsCYP2D6isresponsibleforthemetabolismofanumberofdifferentdrugsAntidepressants,antipsychotics,analgesics,cardiovasculardrugsOver100polymorphismsinCYP2D6havebeenidentifiedBasedonthesepolymorphisms,patientsarephenotypicallyclassifiedas: Ultrarapidmetabolizers(UMs)Extensivemetabolizers(EMs)Poormetabolizers(PMs)第30頁/共87頁CYP2D6PhenotypesNEJM2003;348:529RodenDMetal.AnnInternMed2006;145:749-57第31頁/共87頁CYP2D6PolymorphismsandPsychiatricDrugResponseIncreasedrateofadverseeffectsinpoormetabolizersduetoincreasedplasmaconcentrationsofdrug:Fluoxetine(Prozac)deathinchildattributedtoCYP2D6poormetabolizergenotypeSideeffectsofantipsychoticdrugsoccurmorefrequentlyinCYP2D6poormetabolizersCYP2D6poormetabolizerswithseverementalillnesshadmoreadversedrugreactions,increasedcostofcare,andlongerhospitalstays第32頁/共87頁CYP2D6andCodeineCodeinerequiresactivationbyCYP2D6inordertoexertitsanalgesiceffectDuetogeneticpolymorphisms,2-10%ofthepopulationcannotmetabolizecodeineandareresistanttotheanalgesiceffectsInterindividualvariabilityexistsintheadequacyofpainreliefwhenuniformdosesofcodeinearegiven第33頁/共87頁Strattera?(Atomoxetine)

TreatmentofattentiondeficithyperactivitydisorderCYP2D6poormetabolizershave10-foldhigherplasmaconcentrationstoagivendoseofSTRATTERAcomparedwithextensivemetabolizersApproximately7%ofCaucasiansarepoormetabolizersHigherbloodlevelsinpoormetabolizersmayleadtoahigherrateofsomeadverseeffectsofSTRATTERA第34頁/共87頁CYP2C19andProtonPumpInhibitorsProtonpumpinhibitorsareusedtotreatacidrefluxandstomachulcersUlcercureratesusingomeprazoleandamoxicillinbyCYP2C19phenotype:

CureRate

Rapidmetabolizers 28.6%Intermediatemetabolizers 60%Poormetabolizers 100%

Furuta,T.et.al.AnnInternMed1998;129:1027-1030第35頁/共87頁RocheAmpliChip:FDA-Approved第36頁/共87頁RocheAmpliChipP450TestTheRocheAmpliChipCYP450Testisintendedtoidentifyapatient'sCYP2D6andCYP2C19genotypefromgenomicDNAextractedfromawholebloodsample. InformationaboutCYP2D6andCYP2C19genotypemaybeusedasanaidtocliniciansindeterminingtherapeuticstrategyandtreatmentdosefortherapeuticsthataremetabolizedbytheCYP2D6orCYP2C19geneproduct.第37頁/共87頁Thiopurine-S-Methyltransferase(TPMT)ThiopurinedrugsareusedtotreatcancerAcutelymphoblasticleukemiaTPMTisimportantformetabolizingthiopurinesazathioprine,mercaptopurine(6-MP)PolymorphismsintheTPMTgeneresultindecreasedTPMTenzymeactivityDecreasedTPMTactivitypredisposesindividualstosevere,life-threateningtoxicitiesfromthesedrugs

第38頁/共87頁VariabilityinTPMTActivity第39頁/共87頁Genotype-Guided6-MPDosingPharmacogenomics2002;3(1):89-98.

第40頁/共87頁6-MercaptopurinePrescribingInformationThereareindividualswithaninheriteddeficiencyoftheenzymethiopurinemethyltransferase(TPMT)whomaybeunusuallysensitivetothemyelosuppressiveeffectsofmercaptopurineandpronetodevelopingrapidbonemarrowsuppressionfollowingtheinitiationoftreatment.Substantialdosagereductionsmayberequiredtoavoidthedevelopmentoflife-threateningbonemarrowsuppressioninthesepatients.第41頁/共87頁ImuranPrescribingInformation TPMTgenotypingorphenotypingcanbeusedtoidentifypatientswithabsentorreducedTPMTactivity.

PatientswithloworabsentTPMTactivityareatanincreasedriskofdevelopingsevere,life-threateningmyelotoxicityfromIMURANifconventionaldosesaregiven.

PhysiciansmayconsideralternativetherapiesforpatientswhohaveloworabsentTPMTactivity(homozygousfornon-functionalalleles).IMURANshouldbeadministeredwithcautiontopatientshavingonenon-functionalallele(heterozygous)whoareatriskforreducedTPMTactivitythatmayleadtotoxicityifconventionaldosesaregiven.DosagereductionisrecommendedinpatientswithreducedTPMTactivity.第42頁/共87頁TPMTandThioguaninesClinicalimplications:GenetictestingforTPMTisroutinepracticeatsomecancercentersforprotocolsinvolvingthiopurinedrugsCLIAapprovedtestavailableImplicationsforcancer,transplant,rheumatoidarthritis,lupus,dermatology,andCrohn’sdiseasetreatment第43頁/共87頁DrugTargetPharmacogenomics第44頁/共87頁DrugTargetPharmacogenomicsDirectproteintargetofdrugReceptorEnzymeProteinsinvolvedinpharmacologicresponseSignaltransductionproteinsordownstreamproteinsPolymorphismsassociatedwith diseaserisk“Disease-modifying”polymorphisms“Treatment-modifying”polymorphismsPOLYGENIC第45頁/共87頁ComplexityofDrugEffect第46頁/共87頁AssessingPhenotypeinDrugTargetPharmacogenomicsDepression—SymptomratingscalesIndirectmeasureofdrugresponseInter-raterreliabilityHypertension—BloodpressureMinutetominuteanddiurnalvariabilityInfluenceofenvironmentalfactors(e.g.lackofrestbeforemeasurement)Diabetes—BloodglucoseDiurnalvariationinbloodglucoseInfluenceofenvironmentalfactors(e.g.diet/exercise)第47頁/共87頁ComparisonDrugMetabolismPgx

Polymorphismsoftenleadtonon-functionalorabsentproteinsDistinctphenotypesBimodal/trimodaldistributionPhenotypesareeasilymeasuredDrugconcentrationInvitrocatalyticactivityDrugTargetPgxPolymorphismsusuallydon’tresultinlackofproteinfunction“Subtle”effectsDifferencesinphenotypesaresmallerMeasurementofphenotypesisdifficultImpreciseandvariableFailuretoconsiderhaplotypesJohnsonJAandLimaJJ.Pharmacogenetics2003;13:525-534第48頁/共87頁ExamplesofDrugTargetPharmacogenomicsEvansWE.NEJM2003;348:538-48第49頁/共87頁ExamplesofDiseaseorTreatmentModifyingPharmacogenomicsEvansWE.NEJM2003;348:538-48第50頁/共87頁Beta-blockersand

Hypertension(HTN)HTNisthemostprevalentchronicdiseaseintheUSandacontributortomorbidityandmortalityBeta-blockersarefirst-lineagentinthetreatmentofHTNMarkedvariabilityinresponsetobeta-blockers30-60%ofpatientsfailtoachieveadequatebloodpressureloweringwithbeta-blockersCommonbeta-blockersusedinHTN:MetoprololAtenolol第51頁/共87頁Podlowski,etal.JMolMed2000;78:90.Beta-1AdrenergicReceptorCodon49SerGlyCodon389ArgGly第52頁/共87頁Beta-1ReceptorPolymorphismsandResponsetoMetoprololJohnsonJAetal.ClinPharmacolTher2003;74:44-52第53頁/共87頁Beta-2AdrenergicReceptorPolymorphismsandResponsetoAlbuterolinAsthmaHyperreactivityoftheairwaysisthehallmarkofasthmaAirwaysmoothmusclecontainsbeta-2receptorsthatproducebroncodilationAlbuterolisabeta-2agonistthatisusedinthetreatmentofasthmaProducessmoothmusclecellrelaxationandbronchodilationForcedexpiratoryvolumein1second(FEV1)Phenotypicmeasureofresponse第54頁/共87頁Beta-2Polymorphismsand

ResponsetoAlbuterolLimaJJ.ClinPharmacolTher1999;65:519-25Single8mgalbuteroldoseAlbuterol-evokedincreasesinFEV1werehigherandmorerapidinArg16homozyotescomparedwithGlycarriersCodon16polymorphismisadeterminantofbronchodilatorresponsetoalbuterolLimaJJetal.ClinPharmacolTher1999;65:519-25第55頁/共87頁VKORandWarfarinWarfarinworksbyinhibitingVitaminKEpoxideReductase(VKOR)VKORhelpsrecyclevitaminKwhichisimportantinproperfunctioningofclottingfactorsByinhibitingVKOR,warfarinaltersthevitaminKcycleandresultsintheproductionofinactiveclottingfactorsPolymorphismsexistinthegeneforVKOR(VKORC1)第56頁/共87頁VKORC1GenotypeandWarfarinDoseRequirements33mg/wk46mg/wk21mg/wkG/GG/AA/A第57頁/共87頁WarfarinPharmacogenomicsCYP2C9SNPsaccountforasmallamountofvariabilityinwarfarindoses(~10%)VKORC1SNPsexplainalargerportionofvariabilityinwarfarindoses(~20-25%)Almost50%ofvariabilityinwarfarindosescanbeexplainedbyacombinationoffactors:VKORC1SNPsCYP2C9SNPsNon-geneticfactors(age,weight,concomitantdrugs,concomitantdiseasestates)第58頁/共87頁WarfarinPharmacogenomicsCurrentStatus:DevelopandvalidatedosingalgorithmstothatincludeVKORC1geneticinformation,CYP2C9geneticinformation,andnon-geneticfactors(e.g.,age,weight,concomitantdrugs,concomitantdiseasestates)Testifdosingwarfarinbasedongenotypeisbetterthanthe“usual”careapproach第59頁/共87頁AbacavirHypersensitivityAntiretroviralusedfortreatmentofHIV5%ofpatientsexperiencehypersensitivityreactionstothedrugHypersensitivityisfatalinrarecasesHypersensitivityreactionstartswithsevereGIsymptoms,followedbyfeverandrashDiscontinuationofdrugreversessymptomsRe-challengeofabacavirinhypersensitiveindividualscanresultinlife-threateninglowbloodpressureordeathLancet2002;359:727-32.第60頁/共87頁AbacavirHypersensitivityHypersensitivitytypicallybelievedtobeanimmunologicreactionHypersensitivitymightbegeneticallylinked,andthuspredictableMajorhistocompatibilityproteins(MHC)investigatedbecauseofknownlinksinotherimmuneresponsesandallergicreactions第61頁/共87頁GeneticsofAbacavirHypersensitivityPatientswiththeHLA-B*5701variantwere117timesmore likelytobehypersensitivetoabacavirthanthosewhodid nothavethevariant13patientshad3linkedgeneticvariants(*5701,DR7,DQ3) andallpatientswereabacavirhypersensitiveAllabacavirhypersensitivepatientswereCaucasian,therefore studiesinotherracialgroupsareneededWesternHIVAustraliaHIVCohortStudy第62頁/共87頁DiseaseRiskPolymorphismsPolymorphismscanpredisposeindividualstoadiseaseorincreasetheriskfordiseaseIfadrugwithaknownadverseeffectisgiventoapersonwithageneticsusceptibilitytothatadverseeffect,thereisanincreasedlikelihoodforthatadverseeffect第63頁/共87頁ClottingFactorPolymorphisms,BloodClots,andOralContraceptivePillsPolymorphismsexistinclottingfactorgenesOralcontraceptivepillsaloneareassociatedwithanincreasedriskofbloodclotsWomenwhohaveclottingfactorpolymorphismsareatanevengreaterriskforbloodclotsiftheyreceiveoralcontraceptivepills第64頁/共87頁OralContraceptivePillsandBloodClotsMartinelliI.Pharmacogenetics2003;13:589-594PatientsonOCPwhoarehomozygousforFactorVLeidenhave

50to100-foldincreasedriskofVTEHeterozygotes第65頁/共87頁ADifferentAspectof

DrugTargetPharmacogenomicsInalloftheexamplesthusfar,thedrugtargethasbeenahumanproteinThegeneencodingthathumanproteinhasgenerallyNOTundergonemutationduringthepatient’slifeHowever,intheareasofinfectiousdiseasesandcancer,thedrugtargetisoftenanon-humanproteinCancer:TumorDNAInfectiousDiseases:Viralgenotypee.g.,HIV,HBV,HCV第66頁/共87頁HER-2ProteinandHerceptinHerceptin(trastuzumab):MetastaticbreastcancerTargetstumorcellsthatover-expressthehumanepidermalgrowthfactorreceptor2(HER2)proteinBestresponseattainedinwomenwhoover-expresstheHER2proteinHER-2over-expressioninbreastcancercellsshouldbedonebeforepatientsreceivethedrug第67頁/共87頁Herceptin:PrescribingInformationHERCEPTIN(Trastuzumab)asasingleagentisindicatedforthetreatmentofpatientswithmetastaticbreastcancerwhosetumorsoverexpresstheHER2proteinandwhohavereceivedoneormorechemotherapyregimensfortheirmetastaticdisease.HERCEPTINshouldbeusedinpatientswhosetumorshavebeenevaluatedwithanassayvalidatedtopredictHER2proteinoverexpression第68頁/共87頁HepatitisCInterferon--2bandribavirinareusedtotreatpatientswithhepatitisCvirusDifferentmutationsexistinthehepatitisCvirusKnowledgeofaperson’shepatitisCgenotypemayhelpplayaroleinthetherapeuticdecision-makingprocess

第69頁/共87頁HIVandAntiretroviralDrugsResistancetoantiretroviralagentshindersthemanagementofHIVdiseaseInthevirus,mutationsoccurwhichconferdrugresistanceKnowledgeofviralgenotype(orphenotype)canhelpguidetheselectionofantiretroviraltherapy第70頁/共87頁ChallengesFacingtheFieldofPharmacogenomicsMultiplestudies,butliteratureisinconclusiveinsomeinstancesGeneticsaccountsforaninsufficientpercentageofresponsevariabilityforagivendrugFewstudiesdocumentinggenotype-guidedtherapyisbetterthanthe“usualcare”approachFew“point-of-care”testsavailabletodetermineaperson’sgeneticmake-uporproteinexpression第71頁/共87頁PotentialReasonsforDiscrepanciesInadequatelypoweredstudiesStudyingdifferentdrugresponsephenotypesStudyingdifferentpatientpopulations(differencesinallelefrequencies)ProblemspreciselymeasuringphenotypeSubtletyoffunctionaleffectsofpolymorphismsFocusonsingleSNPsinsteadofhaplotypesFailuretoconsiderthecomplexityofdrugresponseJohnsonJAandLimaJJ.Pharmacogenetics2003;13:525-534第72頁/共87頁第73頁/共87頁第74頁/共87頁PharmacogeneticsandPharmacogenomicsKnowledgeBase(PharmGKB)PubliclyaccessibleknowledgebaseGoal:establishthedefinitivesourceofinformationabouttheinteractionofgeneticvariabilityanddrugresponseStoreandorganizeprimarygenotypingdataCorrelatephenotypicmeasuresofdrugresponsewithgenotypicdataCuratemajorfindingsofthepublishedliteratureProvideinformationaboutcomplexdrugpathwaysHighlightgenesthatarecriticalforunderstandingpharmacogenomics第75頁/共87頁RoleofPharmacogenomicsintheDrugDevelopmentProcess80%ofproductsthatenterthedevelopmentpipelineFAILtomakeittomarketPharmacogenomicsmaycontributetoa“smarter”drugdevelopmentprocessAllowforthepredictionofefficacy/toxicityduringclinicaldevelopmentMaketheprocessmoreefficientbydecreasingthenumberofpatientsrequiredtoshowefficacyinclinicaltrialsDecreasecostsandtimetobringdrugtomarket第76頁/共87頁PharmacogenomicParadigmintheDrugDevelopmentProcessCurrentOptions OptionswithPharmacogenomicsProportionofpatientsshowingpoorornoresponseLowHighContinueclinicaltrialstomarketAbandondrugbeforemarketOptimizeclinicaltrials,makingthemsmallerandshorterContinuetrialssafelybyexcludingat-riskpts第77頁/共87頁PersonalizedMedicineandthePharmaceuticalIndustryTargetedTherapies:Herceptin:treatmentofHER2positivemetastaticbreastcancerGleevec