PharmacogenomicsIndividualized Care:Efforts and EffectsBy:Minal MehtaBiochem118Spring, 2001Current ScenePeople expect individual treatment in allspheres of lifeThe “one-size-fits-all” approach toprovision of drugs is clumsyInter-patient variability in response todrugs is the rule and not the exceptionFacts and FiguresOnly a third of patients takings prescriptivemedicines actually derive their intendedbenefitAdverse drug reaction (ADR) is one of the topsix leading causes of death in the U.S.Serious ADRs – 6.7% (2,216,000 people in1994)Fatal ADRs – 0.32% (106,000 people in 1994)What Next?Inter-individual variation in the efficacy andtoxicity of drugs is largely determined bygenetic factorsUnderstanding the molecular basis of drugaction and genetic determinants of drugresponse should enlighten our use of manymedicationsThe ultimate goal is to give the right drug atthe right dose to the right patient at the righttimePharmacogenomicsField of new drug development based onrapidly increasing knowledge of all genes inthe human genomeStudy of the impact of genetic variation in theefficacy and toxicity of drugsRepresents the genetic basis of a drug’sabsorption, distribution, metabolism,excretion an receptor-target affinityDelivers 3 main genomics-based products:therapeutics, diagnostics and informationGrowth of PharmacogenomicsSystematic discovery of genetic variance canprovide important, achievable opportunitiesfor developing new therapeutic anddiagnostic products from genomicsEmergence of appropriate methods fordiscovery and analysis of genetic variation inhuman populationsThe emergence of managed care as aneconomic incentive for the use ofpharmacogenomicsWe need to analyze the effort inpharmacogenomics from severalperspectives: ethical, legal, practical,financial and commercialUses of PharmacogenomicsAnalgesic effect from codeine (andother effects) that relate to the sixmajor families of cytochrome P450enzymesRelation of effect of tacrine on patientswith Alzheimer’s based on APO E4Effect of a polymorphism in the B-adrenergic receptor gene on asthma…and MoreTrastuzumab in the treatment of breastcancerPolymorphisms in dopamine receptorsand migraine symptomsMethodsSNPs. Single SNPs and positioning andinteraction of several SNPs in haplotypesPharmacogenomic candidate gene validationrelies on:Identification of candidate pharmacogenomic target genesIdentification of all potential alleles for theseGenotyping of a clinically relevant population for the set ofrelevant allelesApplication of robust statistical methods to establish linkagebetween any allele and a selected response/nonresponsephenotypeToolsSubtractive cloningDifferential displayEST sequencingcDNA Microarray HybridizationSerial Analysis of Gene ExpressionManagementThe Pharmacogenetics Research Network andKnowledge BaseHas the capacity to collect geneticinformation, detect polymorphic variants,identify the functional consequences ofvariation, and correlate this information withdrug responsesThe network consists of research groups thatreceive funding from NIH to contribute to thedevelopment of and add data to a databaseKnowledge Base (PharmGKB)Being developed by Russ B. Altman,Stanford UniversityInterlink genomic, molecular, cellularand clinical information about genesystems important for modulating drugresponsesFlexibility, security and stabilityAbsolute confidentialityAnalysisBioinformatics has been key in development ofpharmacogenomicsSoftware has been developed that captures theexperimental data and compares results withexisting genome databases, generatesdendrograms for sequence homology, andrecognizes patternsSpawned the field of in-silico biology, in whichmining of computer databases for genomicinformation is performed without laboratoryexperimentationChallenges (Scientific)Identification of new disease-relatedgenes -> new targets to pursueImprovement of technologyChallenges (Non-scientific)Financial ViabilityEthical IssuesFinancial Viability (forPharmaceutical Firms)Opportunities for the development ofcustomized drugsReintroduction of older drugs which areeffective in certain individualsHowever, reduced market from which toregain investmentDifficult to predict how many NCEs might beapproved on the basis of pharmacogenomicstudiesEthical ConsiderationsIf drugs are tested against the commonpolymorphisms of the USA or Europe, should theresults be applied to people who for reasons oftheir own refuse genetic testing?Would it be illegal or unethical to try it in patientswho do not match the genetic profile of the trialparticipants who achieved benefit?Are genetics even likely to be the majordeterminant of treatment response given thatenvironmental and social factors play such alarge role on disease response?Ethical ConsiderationsWill people with rare genetic profiles simplynot be studied to cut down on costs?Genotyping in both clinical research trials andeventually, clinical practice will becomeroutine. The genotype could be misusedRisk-benefit analysis: to be justifiable ethically,clinical research must produce benefits andeither prevent or minimize possible risksEthical ConsiderationsShould pharmaceutical companies conductinga clinical trial or marketing a particular drugbe obliged to offer genotyping to patientsgiven the doing so might lead to reductions intheir potential markets?Serious consequences if drugs are given tothe wrong group of peopleLess ethical controversy than otherapplications of geneticsThe Future …Optimistic view: “In the future, before a doctor prescribes amedicine, the doctor will take some blood, haveit analyzed at a nearby lab and identify which of,let’s say, 12 drugs are most likely to treat thepatient effectively with minimum side effects,”- Allan D. Roses, vice president and worldwidedirector of genetics research at Glaxo-Wellcome.The Future … a More RealisticViewEnormous promise, but will have the greatestinitial benefit in developed countries, owing toexpense, availability of resources and thefocus of initial researchMost likely, it will take 3 or 4 examples beforethe regulatory agencies feel comfortableissuing guidelines. In the meantime,companies will have to work closely withregulatory bodies to work out where geneticdata is going to be useful.- “At present drugs are picked out on thebasis of whether they are not going to putpeople at risk”, says Jerry Colins of theFDA. “One day, we will be picking outdrugs on the basis that they are going totreat people
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