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ClinicalAdoptionofPharmacogenomics
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ImplicationsforEducatorsandProviders
AniwaaOwusuObeng,PharmDAssistantProfessorIcahnSchoolofMedicineatMountSinaiTheCharlesBronfmanInstituteforPersonalizedMedicineDivisionofGeneralInternalMedicine
ClinicalPharmacogenomicsCoordinatorTheMountSinaiHospitalPharmacyDepartment
August2nd,2016
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Objectives• Describetherelevanceofgenomicstomedicaleducationandclinicalcarebyusingapatientcaseexample.• Explorethepotentialclinicalbenefitsofpharmacogenomics• Describetheclinicalimplementationprocessforpharmacogenomicsinamedicalinstitution.• Discussresourcestofacilitatepersonalandprofessionalgenomicseducation.
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MeetMr.PGx• 54yearoldmalepresentedtothecardiaccatheterizationlaboratoryforaleftheartcath duetoanabnormalstresstreadmillstudyandchestpain• PMH:• Hypercholesterolemia,coronaryarterydisease
• Intervention:• Drugelutingstentinhismid-circumflexcoronaryartery
• PGx:• MDorderedPGxtestbutsamplewasnotcollected
• Patientdischargedonclopidogrel75mgandaspirin81mgdaily
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CurrentMedicalPractice
• Afterdiagnosis,patientsareprescribedtherapywithnoreferencetothepatient’sgeneticinformation
• “Trialanderror”or• “Onesizefitsall”
PersonalizedMedicine.BayerHealthCare:Scienceforabetterlife.2013.AccessedonApril16,2013.[Internet].Availablefrom:http://www.bayerpharma.com/en/research-and-development/research-focus/oncology/personalized-medicine/index.php
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AdverseDrugEvents
Budnitz DS,LovegroveMC,Shehab N,etal.NEJM2011;365:2002- 12
2007– 2009:pts > 65years99,628annualhospitalizations
166,174annualEDvisits
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FactorsthatInfluenceMedicationResponse
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Genetics
HussarDA.OverviewofResponsetoDrugs.April2007.AccessedonJuly23,2015.[Internet]Availablefrom:http://www.merckmanuals.com/home/drugs/factors_affecting_response_to_drugs/overview_of_response_to_drugs.html
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TheHumanGenomeProject
• 13yearinternationalprojectcompletedin2003
• CoordinatedbyUSDepartmentofEnergyandtheNIH
• Projectgoals:• IdentifyallgenesinhumanDNA• Determinethesequencesofthe3billionchemicalbasepairs
• Storetheinformationindatabases• Improvetoolsfordataanalysis• Transferrelatedtechnologiestotheprivatesector
• Addresstheethical,andsocialissuesthatmayarise
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June26,2000
HumanGenomeProjectinformation.UpdatedonJuly31,2012.AccessedonJuly23,2015.[Internet].Availablefrom:http://www.ornl.gov/sci/techresources/Human_Genome/home.shtml
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TheNewEraofMedicalPractice• PersonalizedMedicine• “Emergingpracticeofmedicinethatusesanindividual’sgeneticprofiletoguidedecisionsmadeinregardtotheprevention,diagnosis,andtreatmentofdisease” - NationalHumanGenomeResearchInstitute
• FirstcoinedinApril1999• RobertLangreth andMichaelWaldholzinWSJ,laterinTheOncologist
• Alsoknownas:• Individualizedmedicine• Precisionmedicine
PersonalizedMedicine.GeneticsHomeReference.UpdatedonApril7,2013.AccessedonApril16,2013.[Internet].Availablefrom:http://ghr.nlm.nih.gov/glossary=personalizedmedicine
Jørgensen J T The Oncologist 2009;14:557-558
Numberofarticlesperyearthatincludedtheterm“personalizedmedicine”
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Pharmacogenomics
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Imageaccessedfrom:http://mytorontocanadambastudentexperience.blogspot.com/2012/10/personalized-medicine-or-p4-medicine.html
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CYP2C19&CLOPIDOGRELAPGXEXAMPLE
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CYP2C19andClopidogrel
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Clopidogrel IntestinalAbsorption
2-oxo-clopidogrel
ActiveMetabolite
SR-26334
15%
Esterases85%
2C19,1A2,2B6
2C19,3A4/5,2B6
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CytochromeP4502C19• CYP2C19isahepaticenzyme• Metabolizesabout5-15%ofallprescriptiondrugs• Variationsingenotypicinheritanceandhepaticexpressions• Phenotypicvariabilityinsubstratemetabolism
• Nonfunctionalmetabolicactivity• CYP2C19*2,*3,*4,*6,*7,*8
• Decreasedmetabolicactivity• CYP2C19*9&*10
• Increasedmetabolicactivity• CYP2C19*17 18
Lima,J.et.al.(2014).Pharmacogenomictesting:thecaseforCYP2C19protonpumpinhibitorgene-drugpairs.Pharmacogenomics,1405-1415
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CYP2C19GenotypesandPhenotypes
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Phenotype Genotype/Activity DiplotypesExamples
PopulationFrequency
Ultra-rapidmetabolizer(UM)
Carrieroftwo increasedactivityallelesORonenormalplusoneincreasedactivity
allele
*17/*17;*1/*17 ~5– 30%
Extensivemetabolizer(EM)
Wildtype(carrieroftwonormalfunctionalleles)
*1/*1 ~35– 50%
Intermediatemetabolizer(IM)
Carrierofonefunctionalandoneloss offunctionORonelossoffunctionandoneincreasedactivityallele
*1/*2;*2/*17 ~18– 45%
Poormetabolizer(PM)
Carrieroftwolossoffunctionalleles
*2/*2;*3/*3 ~2– 15%
ScottSAetal.(2013).ClinicalPharmacogeneticsImplementationConsortiumGuidelinesforCYP2C19GenotypeandClopidogrelTherapy:2013Update.CPT,94(3):317- 323
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CYP2C19PolymorphismsandResponsetoClopidogrel
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MegaJL,etal.NEJM2009;360:354- 62
Carriersofareduced-functionCYP2C19allelehavesignificantlylowerlevelsoftheactivemetaboliteofclopidogrel,diminishedplateletinhibition,anda
higherrateofmajoradversecardiovascularevents,includingstentthrombosis.
RiskofdeathfromCVcauses,myocardialinfarctionorstroke
Defin
iteorP
robable
Sten
tThrom
bosis(%
)
Prim
aryEfficacyOutcome(%
)
StentThrombosis
DayssinceRandomization DayssinceRandomization
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PGxResources• PharmGKB• PharmacogenomicsKnowledgeBase
• Collects,curatesanddisseminatesknowledgeabouttheimpactofhumangeneticvariationondrugresponses
• CPIC• ClinicalPharmacogeneticsImplementationConsortium
• Peer-reviewedguidelines
• DesignedtohelpcliniciansunderstandHOW availablegenetictestresultsshouldbeusedtooptimizedrugtherapy
• Freelyaccessibleonline
• EndorsedbyASHP,ASCPTandotherexternalnetworks
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PharmGKB.CPIC:ClinicalPharmacogeneticsImplementationConsortium.[Internet].Availablefrom:https://www.pharmgkb.org/page/cpic
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CYP2C19-GuidedAntiplateletTherapyPhenotype ClinicalImplications
onClopidogrelTherapeuticRecommendations
LevelofRecommendations
Ultra-rapidMetabolizer
Increasedplateletinhibition
Useclopidogrelatlabelrecommendeddoses
Strong
ExtensiveMetabolizer
Normalplateletinhibition
Useclopidogrelatlabelrecommendeddoses
Strong
IntermediateMetabolizer
Reducedplateletinhibition,increasedriskofadverseCVevents
Usealternativeantiplatelettherapy(i.e.prasugrelorticagrelorifnotcontraindicated)
Moderate
PoorMetabolizer
Significantlyreducedplateletinhibition,increased riskofadverseCVevents
Usealternativeantiplatelettherapy(i.e.prasugrelorticagrelorifnotcontraindicated)
Strong
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ScottSA,etal.CPT2013;94(3):NEJM2009;360:317-323
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PGxClinicalImplementationProcess
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CPICguidelines
FDAPGxlabeling&/ormostevidenceonPGx
influence
ClinicianInitiated
TEAMEFFORTPharmacists,physicians,expertsinlab,informatics,genetics,health-
systemadministrationsupport,adminstaff,medicaltrainees
MedSafetyIssues
PGxSubcommittee
P&TCommittee
STANDARDCLINICALPRACTICE
IRB
CLINICALRESEARCHPROJECT
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Mr.PGxcontinued• Presentedtoemergencyroom2daysafterdischarge• CC:chestpain,substernalchestpressureassociatedwithleftarmheavinessanddiaphoresis
• CardiologyIntervention:• Twooverlappingdrugelutingstentstorightcoronaryartery
• PGxTeam:• FollowedupwithMDthenextdaytoreorderPGx• AdaylaterthePGxtestwasreorderedandsamplecollected
• Dischargedontheday4onclopidogrel75mgandASA81mgdailyawaitingPGxresults• PGxtestresultedas*2/*2(poormetabolizer)onday5• Clopidogrelwaschangedtoprasugrel10mgdaily 24
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KeyRolesinClinicalPGx
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• Advocates• Advocateforthetherapeuticapplicationsofpharmacogenomicsinpractice.
• TranslationalResearchers• To validate and standardize genetic markers and genetic testing for drugtherapy
• To guide and accelerate the application of pharmacogenomics to clinicalpractice
• ClinicalImplementators• Inclusionofpharmacogenomictestresultsinmedicalandpharmacyrecords
• Educators• Prescribers,nurses,pharmacistsandpatients
• Students• Useofpharmacogenomicsandincorporationintoprofessionalhealthcarecurricula.
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WhatwentwronginMr.PGx’scase?
• HowcanweimprovePGxeducationfor:• Physiciansassistants?• Nurses?
• WhatarethechallengestoPGxeducationandhowcanweovercomethem?
• WhataretherolesoffacultyandcliniciansintheclinicaladoptionofPGx?
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ClinicalAdoptionofPharmacogenomics
.
ImplicationsforEducatorsandProviders
AniwaaOwusuObeng,PharmDAssistantProfessorIcahnSchoolofMedicineatMountSinaiTheCharlesBronfmanInstituteforPersonalizedMedicineDivisionofGeneralInternalMedicine
ClinicalPharmacogenomicsCoordinatorTheMountSinaiHospitalPharmacyDepartment
[email protected] ,2016
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