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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

GENETICS101

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

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

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

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

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

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

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

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

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

Mr.PGxcontinued• Presentedtoemergencyroom2daysafterdischarge• CC:chestpain,substernalchestpressureassociatedwithleftarmheavinessanddiaphoresis

• CardiologyIntervention:• Twooverlappingdrugelutingstentstorightcoronaryartery

• PGxTeam:• FollowedupwithMDthenextdaytoreorderPGx• AdaylaterthePGxtestwasreorderedandsamplecollected

• Dischargedontheday4onclopidogrel75mgandASA81mgdailyawaitingPGxresults• PGxtestresultedas*2/*2(poormetabolizer)onday5• Clopidogrelwaschangedtoprasugrel10mgdaily 24

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.

WhatwentwronginMr.PGx’scase?

• HowcanweimprovePGxeducationfor:• Physiciansassistants?• Nurses?

• WhatarethechallengestoPGxeducationandhowcanweovercomethem?

• WhataretherolesoffacultyandcliniciansintheclinicaladoptionofPGx?

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ANYQUESTIONS?

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ClinicalAdoptionofPharmacogenomics

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ImplicationsforEducatorsandProviders

AniwaaOwusuObeng,PharmDAssistantProfessorIcahnSchoolofMedicineatMountSinaiTheCharlesBronfmanInstituteforPersonalizedMedicineDivisionofGeneralInternalMedicine

ClinicalPharmacogenomicsCoordinatorTheMountSinaiHospitalPharmacyDepartment

Aniwaa.owusu-obeng@mssm.eduAugust2nd,2016

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