药物安全性中的药物基因组学策略

药物安全性中的药物基因组学策略的介绍

DrugDiscoveryToday:TherapeuticStrategies

Editors-in-Chief

RaymondBaker–formerlyUniversityofSouthampton,UKandMerckSharp&Dohme,UKEliotOhlstein–GlaxoSmithKline,USA

DRUG DISCOVERY

Vol.xxx,No.xx2011

STRATEGIES

Genetics,drugdiscoveryandclinicaldevelopments

Pharmacogenomicstrategiesin

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drugsafety

MichaelA.Pacanowski*,IssamZineh

GenomicsGroup,Of ceofClinicalPharmacology,Of ceofTranslationalSciences,CenterforDrugEvaluationandResearch,U.S.FoodandDrugAdministration,SilverSpring,MD20993,UnitedStates

Drugsafetyisapriorityfordrugdevelopersandreg-ulatoryagencies.Pharmacogenomicsisapowerfultoolthatcanbeusedtomanageclinicalrisksaswellasresolvethemechanisticbasisofadversedrugevents.Advancesinthescienceofdrugsafety,increasedcommitmenttopharmacogenomicsbydrugcompanies,andenhancedregulatoryreviewinfra-structureattheU.S.FDAhavehelpedtoadvancetheapplicationofsafetypharmacogenomicsindrugdevelopmentandpublichealthdecision-making.Thisreviewhighlightssomesuccessesindiscoveryandtranslationofpharmacogenomicbiomarkersforadversedrugeventsandoutlinesfuturestrategiestooptimizethedevelopmentandclinicalapplicationofpharmacogenomicinformation.

Sectioneditors:

RichardWooster–GlaxoSmithKline,CancerMetabolismDrugDiscovery,Collegeville,PA19426,USA.

LonCardon–GlaxoSmithKline,KingofPrussia,PA,USA.

Introduction

Adversedrugexperiences(ADEs)manifestinarangeofeventsfromcommon,pharmacologicallyanticipatedtoxicitiestotherapeuticfailurestorare,severeidiosyncraticdrugreac-tions.Drugsafetyisatoppriorityfordrugdevelopersandregulatoryagenciesbecausetoxicologicalandclinicalsafetyissueshaltthedevelopmentofapproximatelyoneinthreedrugs[1].AlthoughsomeADEscanbepredictedfromexperi-mentalmodelsandmanagedbycarefulpatientselectionor

ConceptsinthispaperwerepartlypresentedattheDrugInformationAssociationmeetingonCardiovascularSafetyinDrugDevelopment:QT,Arrhythmias,Thrombosis,andBleedingonApril13,2010.

*Correspondingauthor.:M.A.Pacanowski(Michael.Pacanowski@fda.hhs.gov)1740-6773/$.PublishedbyElsevierLtd.

DOI:10.1016/j.ddstr.2011.04.002

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dosemodi cation,novelstrategiestomitigateandmanageemergentsafetyissuesareneededtofosterthedevelopmentofvaluabledrugs.

PharmacogenomicsisapowerfultoolthatcanbeusedtomanageclinicalrisksandresolvethemechanisticbasisofADEs.Historically,thelimiteddetectionofADEsinpre-approvalstudies,poorlyde nedsafetyphenotypesandpre-dictionmethods,ambiguouscasede nitions,lackofstoredbiospecimens,andtechnologicallimitationshinderedtheabilitytocharacterizethegeneticunderpinningsofdrugtoxicities.However,thelandscapeofdrugsafetypharmaco-genomicsisevolving.Public–privatepartnerships,consortiadevelopment,large-scalebiobankingprojects,andtheadventofhigh-throughputgenotyping/sequencingtechnologiesarecreatingopportunitiestodiscoverrobust,highlypredictivebiomarkersforadversedrugtreatmentoutcomes.Inaddition,increasedcommitmenttopharmacogenomicsbydrugcom-paniesandenhancedregulatoryreviewinfrastructureattheU.S.FDAhavehelpedtoadvancetheapplicationofsafetypharmacogenomicsindrugdevelopmentandpublichealthdecision-making[2].ThisreviewhighlightssomesuccessesindiscoveryandtranslationofpharmacogenomicbiomarkersforADEs,andoutlinespossiblefuturestrategiestooptimizethedevelopmentandclinicalapplicationofpharmacoge-nomicinformation.

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Pleasecitethisarticleinpressas:Pacanowski,M.A.andZineh,I.Pharmacogenomicstrategiesindrugsafety,DrugDiscovToday:TherStrategies(2011),doi:10.1016/

药物安全性中的药物基因组学策略的介绍

Apharmacogenomicperspectiveondrugsafety:shiftingprobabilities

Drugsafetyissuesaregenerallymanagedusingthreenon-mutuallyexclusivestrategies(Box1):(1)monitoring-basedintervention,(2)carefulpatientselection,and(3)riskcommunication.Drugsthathavemeasurable,chronictoxicitiestendtobemanageable.Forinstance,periodicmonitoringfortheappearanceofknownmetabolicadverseeventsduringantiretroviralorantipsychoticdrugtherapyallowsprescriberstoswitchdrugs,adjustdoses,orstartsupportivetherapies(e.g.,lipid-loweringtherapy).Moni-toringliverfunctiontestresultsfordrugsthatmaycausehepaticinjuryisacommonriskminimizationstrategy.Unfortunately,sometoxicitiesarenotamenabletoclinicalmonitoring.Inthesecases,drugusemayberestrictedtothepatientpopulationswiththegreatestbene t/riskbalance.Assuch,numerousdruglabelsbearwarningsforpopulationsinwhichADEsoccurmorefre-quently,orfocusonselectingpatientsthataremostlikelytobene t.Whentheat-riskpopulationscannotbede nedandthemechanismisunknown,riskmanagementmayfocusonincreasingprescriberandconsumerawarenesssoastoin uenceprescribingormonitoringpatterns.Phar-macogenomicstrategiescouldhavesigni cantvalueinshiftingunpredictable,mechanisticallyuncleareventstopredictable,manageablerisks,providedthedrughasaclearvalue.

Pharmacokinetics,pharmacodynamics,andidiosyncrasy

PharmacokineticADEs

Theriskpro leofdrugsthathavesteepexposure-safetyrelationshipshingeslargelyonpharmacokineticvariability.Toxicitiesthataresensitivetodisturbancesindrugmetabo-lism,mainlybecauseofdruginteractions,accountformanyofthemarketwithdrawalsseeninrecentdecades.Terfena-dine,mibefradil,astemizole,andcisaprideallwerefoundtohaveexposure-relatedtoxicitiesthat,whenco-administeredwithenzyme-inhibitingdrugs,becameapparentinthepost-approvalsetting.Giventhishistory,manypromisingcom-poundsmayneverbedevelopedifsubjecttoextensivemeta-bolismbypolymorphicenzymes.Therefore,consideringthepotentialimpactofpolymorphicdrugmetabolismiscrucialtomaximizingsuccessfuldevelopmentofpotentiallypromis-ingcompounds.

Typically,drugdosageswillbemodi edifsigni cantpharmacokineticinteractionsareobserved.However,extendingthelogicofmetabolicdruginteractionstopoly-morphicmetabolismandtransporthasnotbeenawidelyadoptedconcept.Atpresent,thioridazinerepresentsoneoftheonlydrugswithacontraindicationforuseinageneticallyde nedsubpopulation(CYP2D6poormetabolizers)b …… 此处隐藏：31097字，全部文档内容请下载后查看。喜欢就下载吧 ……