Pharmacogenomics-Applications in Pediatric Oncology - PPAG

3/8/2011Adoption of pharmacogenetic test results intoclinical practice has been slow•Anticipate that over a period of many years, there willbe a gradual increase in evidence to support increasedadoption of genetic tests into clinical practice.•Processes P will be needed dto incorporatepharmacogenetic test results into routine patient care.Steps to Incorporate ClinicalPharmacogenetics at St. Jude Children’sResearch HospitalBackground on ClinicalPharmacokinetics Service• All TDM results verifed by pharmacist• All TDM results accompanied by clinical pharmacy consult6

3/8/2011Clinical Decision Support anIntegral Component• Clinical decision support systems‐ interactivecomputer programs designed to assist clinicianswith decision making tasks.Pharmacist enters abnormal genotypeElectronic flag linked to order for related drugMonitoring TPMT Status Status in ALL Patients in ALL at Patients St JudeNewly dx’d ALL patientsDay 3 of inductiontherapyWeek 7 of continuationtherapyWeek 17 of continuationtherapyTPMT genotype testingby CLIA‐approved labRBC TGN/MeTIMPmeasuredRBC TPMT activitymeasuredResult entered intoelectronic med recordClinical Pharmacy Consultentered into EMRClinical Pharmacy Consultentered into EMRClinical Pharmacy Consultentered into EMRIf patient meets any criteriaFor HET or Homozygous Variant StatusTPMT Status enteredinto Problem List in EMRElectronic flag linkedto thiopurines in EMR6MP Doses adjusted to desired level of myelosuppressionTPMT Genotype Result and PharmacogeneticsConsult Entered into EMR9

3/8/2011Therapeutic Drug Monitoring andClinical Pharmacogenetics• TDM practices have informed our approach, but keydistinction exists• Pharmacogenetics provides a laboratory result that mayimprove dosage individualization‐‐‐without having to givethe drug first• Advantages of pre‐emptive genotyping• Avoids turn‐around issues• Allows ample time to interpret result• Genotype result ready to guide prescribingCYP2D6 and Codeine PharmacogeneticsCYP2D6 is major metabolic pathway forseveral classes of drugs•TCAs (nortriptyline, amitriptyline)•SSRIs (fluoxetine, paroxetine)•Atomoxetine•Tamoxifen•Codeine•Beta blockers (metoprolol)•Anti‐arrhythmics (propafenone, flecainide)10

3/8/2011Frequency• Deficient• V/V• ~ 2‐10%• “PMs”CYP2D6 Drug Metabolism Phenotypesand Gene Polymorphisms• Heterozygous• Wt/V• ~ 30‐40%• “IMs”• Wt/Wt• ~ 60%• “EMs”• GeneDuplication(WT >2 )• ~ 0‐1%• “UMs”Low Enzyme activity/ drug clearance HighTranslating CYP2D6 CYP2D6 Genotype Genotype into Phenotype intoPredictionPhenotype PredictionThe CYP2D6 Activity Score predicted by genotypes can predict the following phenotypes:an AS of 0 = PM, an AS of 0.5 to 1.5 = IM, an AS of 2 = EM and an AS ≥ 2.5 = UM.Table adapted from: Gaedigk A, et al. Clin Pharmacol Ther 2008;83:234.CYP2D6 and Codeine• CYP2D6 catalyzes codeineCodeine metabolism to morphineCYP2D6• Typically a minor pathway• Major pathway in UMs• Inherited enzymeCYP3A4 Morphinedeficiency does notalways mean moreglucuronidation toxicity!Norcodeine• Patients who inheritCYP2D6 deficiency canCodeine-6-glucuronide not activate codeine.11

3/8/2011Monitoring CYP2D6 Genotype in in PatientsSt JudeNewly dx’d ALL patientsDay 15 of inductiontherapyCYP2D6 genotype testingby CLIA –approved labResult entered intoelectronic med recordCYP2D6 Activity Score assigned;Clinical Pharmacy Consultentered into EMREM or IM StatusPM or UM StatusPM or UM Status enteredinto problem listElectronic flaglinked to prescribingof relevant meds in EMRClinical Decision Support:PG result enteredClinical Pharmacy Consult enteredPM or UM status entered into Problem ListElectronic Alert activated when CYP2D6substrate prescribedPatient Case­ ZBCYP2D6 Poor Metabolizer• ZB is a 4 year‐old boy with newly diagnosed ALL,enrolled on frontline treatment on the St. Jude Total16 protocol. He has a whole blood sample obtainedon Day 15 for CYP2D6 genotyping, which gives aresult of *4/*4. The clinical pharmacist uses theCYP2D6 Activity Score table to determine that thepatient is a poor metabolizer.12

3/8/2011Translating CYP2D6 Genotype into PhenotypeCYP2D6 PredictionActivity ScoreThe CYP2D6 AS predicted by genotypes can predict the following phenotypes: an AS of 0= PM, an AS of 0.5 to 1.5 = IM, an AS of 2 = EM and an AS ≥ 2.5 = UM.Table adapted from: Gaedigk A, et al. Clin Pharmacol Ther 2008;83:234.Patient Case­ ZBCYP2D6 Poor Metabolizer• The clinical pharmacist speaks with ZB and hisparents and learns that he has been prescribedcodeine PRN for pain associated with vincristineneuropathy, which has had no effect. Thepharmacist documents the genotype result in theEMR, and recommends starting gabapentin. Thepatient’s pain subsequently resolves.Lab tests andphenotype consult aremodified fromtemplates and enteredinto pt medical record13

3/8/2011Problematic genotypesare entered intoproblem listDecision support:Links problemgenotypes to drugordering, prescribing,and administrationIf a clinician selects amedication that islinked to the specificpharmacogenetic alert(e.g. codeine &CYP2D6), a Warning Boxwill appear with a briefdescription of thepotential problem.The clinician is thendirected to select anappropriate actionbefore proceeding.Summary of ClinicalPharmacogenetics at St. Jude• Modeled after our established TDM service• Current focus on TPMT and CYP2D6 in ALL patients• Represents about 8% of TDM consults each month• Implementation• Pharmacists interpret results, which requiredtraining (e.g., activity score for CYP2D6)• Applying clinical decision support in our electronicmedical record is a key aspectCrews et al. Amer J Health‐Syst Pharm 2011; 68:14314

3/8/2011How will the availability of high­throughputgenotyping change the landscape?• Potential for robust genotyperesults for pennies per test• Only need one test per lifetime• Ability to have multiple resultsready “pre‐emptively”• How do we implement clinicalpharmacogenomics?PGEN4Kids Study: CLINICALIMPLEMENTATION OFPHARMACOGENETICSGoal: migrate pharmacogenetic tests fromlaboratory into routine patient care, to be availablepreemptivelyWhy design a clinical trial aboutimplementing clinicalpharmacogenetics?• Our overarching mission is to establish acomprehensive process to enable clinicians to makegenotype‐guided therapeutic decisions.16

3/8/2011PGEN4Kids will enforce structure on process tomove tests from high‐throughput platform tomedical recordClinicianacceptanceGenotypingPlatformevaluationPatient/familyconsentDetermine eligibility for migratingindividual test resultsProcess for migrating pharmacogeneticsdata to medical recordPGEN4Kids Process for anIndividual Gene• Evaluate evidence for the gene e.g., CYP2C19• Interpret genotypes‐‐ *2, *3, *17• Translate to phenotypes– EM, IM, PM, UM• Prioritize drugs to add– clopidogrel, voriconazole• Move genotype results data to EMR for all patients whohave been tested• Prioritize data for “problem list” and Decision Support• Educate patients, parents, clinicians (at least annually)• Revise, RepeatThe processPGEN4Kids17

3/8/2011All clinical genotype results will be posted in EMRChallenges to defining thisprocess• Deciding what constitutes sufficientevidence to migrate a test into routineclinical care• Need a mechanism through which datacan be vetted and consensus reached fortranslating clinical pharmacogenomic teststo the clinic• Clinical Decision Support is integralCPIC: Clinical PharmacogeneticsImplementation Consortium• Clinicians, scientists, FDA, 3 rd partypayors, patient representatives, socialworkers, etc• Providing updated recommendations ongenotyping and drug dosing18

3/8/2011Relling et al. Clin Pharmacol Ther 201119

3/8/2011Patient Involvement• PGEN4Kids includes patient/familyeducation• Patients/families can choose their level ofinvolvement in the process ofimplementing pharmacogenomicsSt. Jude Family Advisory Council• Great diversity of opinion– From “why are you telling me this” to “I want to decide when thisgoes in record”• High level of interest• Helped to put together educational DVD• Will remain engaged in protocolConclusions• Prospective pharmacogenetic testing in patients witha high likelihood of receiving drugs of interest results in theidentification of patients at high risk for toxicity or lack of benefit.• Clinical decision support can enhance patient safety by providingautomated warnings during the medication prescribing anddispensing processes.• Implementing clinical pharmacogenetics will help to realize thepromise of personalized medicine.20

3/8/2011Potential of Personalized Medicine: Getting the rightdose of the right drug to the right patientReferences1: Stearns V, Johnson MD, Rae JM, et al. Active tamoxifen metaboliteplasma concentrations after coadministration of tamoxifen and theselective serotonin reuptake inhibitor paroxetine. J Natl Cancer Inst.2003 Dec 3;95(23):1758‐64.2: Yang JJ, Cheng C, Yang W, et al. Genome‐wide interrogation ofgermline genetic variation associated with treatment response inchildhood acute lymphoblastic leukemia. JAMA. 2009 Jan 28;301(4):393‐403.3: Ensom MH, Chang TK, Patel P. Pharmacogenetics: the therapeuticdrug monitoring of the future? Clin Pharmacokinet. 2001;40(11):783‐802.4: Gaedigk A, Simon SD, Pearce RE, et al. The CYP2D6activity score: translating genotype information into a qualitativemeasure of phenotype. Clin Pharmacol Ther. 2008 Feb;83(2):234‐42.References5: Crews KR, Cross SJ, McCormick JN, et al. Development andimplementation of a pharmacist‐managed clinicalpharmacogenetics service. Am J Health Syst Pharm. 2011 Jan15;68(2):143‐50.6: Relling MV, Gardner EE, Sandborn WJ, et al. Clinicalpharmacogenetics implementation consortium guidelines forthiopurine i methyltransferase hl genotype and thiopurineidosing. Clin Pharmacol Ther. 2011 Mar;89(3):387‐91. Epub 2011Jan 26.7: McLeod HL, Krynetski EY, Relling MV, Evans WE. Geneticpolymorphism of thiopurine methyltransferase and its clinicalrelevance for childhood acute lymphoblastic leukemia.Leukemia. 2000 Apr;14(4):567‐72.21