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The Current State of Pharmacogenomics
- 1. The Current State of Pharmacogenomics Marti Larriva PharmD Candidate, Class of 2014 University of Arizona
- 2. Objectives Discuss background and relevance of pharmacogenomics Describe current state of pharmacogenomics Lay out a step-wise process for integrating pharmacogenomics into your clinical practice Discuss examples of pharmacists performing pharmacogenomics
- 4. Pharmacogenomics Definition: The genetic influence of your response to drugs
- 5. Relevance FDA pharmacogenetic modifications to >100 drug labels Of top 200 drugs 2003 – 1.5% 2011 – 11% Mayo-Medco Warfarin Effectiveness Study 28-43% reduction in hospitalizations due to thromboembolism or bleeding PREDICT-1 Study – Abacavir (NRTI) 56% reduction in clinical hypersensitivity reactions 100% reduction in immunologically confirmed hypersensitivity reactions Moaddeb J, Haga SB. Therapeutic Advances in Drug Safety. 2013. Mallal S, Phillips E, Carosi G et al. N Engl J Med. 2008;358(6):568-79. Epstein RS, Moyer TP, Aubert RE et al. J Am Coll Cardiol. 2010;55(25):2804-12.
- 6. Current State of Pharmacogenomics How often is it being used?
- 7. 97.6% 29.0% 10.3% 12.9% 26.4% 57.0% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% Believe genetics affects drug response PGx training in med school or postgraduate Feel adequately informed about genetic testing Ordered a PGx test in last 6 mo. Anticipate ordering PGx test in next 6 mo. Test not ordered due to not enough info PercentageofRespondents Medco/AMA Nationwide Physician Survey Key Findings Stanek EJ, Sanders CL, Taber KA et al. Clin Pharmacol Ther. 2012;91(3):450-8.
- 8. CPIC & ASCPT 2009/2010 Survey Challenges: Interpretation of genetic results Translating results into clinical actions Provider resistance Cost of testing and reimbursement CPIC = Clinical Pharmacogenetics Implementation Consortium ASCPT = American Society for Clinical Pharmacology and Therapeutics Relling MV, Klein TE. Clin Pharmacol Ther. 2011;89(3):464-7.
- 10. PBM Facilitated Pharmacogenomic Testing PBMs = Pharmacy Benefits Managers = process prescriptions for groups that pay for drugs (insurance companies or corporations)
- 11. Express Scripts Express Scripts. Services: Personalized Medicine. Available at: http://www.express-scripts.com/services/physicians/personalizedmedicine/ Use Class Drug Gene Concern HIV CCR5 receptor antagonist Maraviroc CCR5 tropism Efficacy Nucleoside reverse transcriptase inhibitor Abacavir HLA- B*5701 Toxicity Cancer Protein kinase inhibitor Imatinib Nilotinib Dasatinib BCR/ABL Efficacy Cardiac Vitamin K antagonist Warfarin CYP2C9 VKORC1 Toxicity Antiplatelet Clopidogrel CYP2C19 Efficacy
- 12. CVS Caremark Use Class Drug Gene Concern HIV Antiretrovirals Abacavir HLA-B*5701 Toxicity Cancer Thiopurines Azathioprine Thioguanine TPMT Efficacy Anti-estrogens Tamoxifen CYP2D6 Efficacy Protein kinase inhibitor Imatinib Nilotinib Dasatinib Erlotinib Lapatinib BCR/ABL Efficacy Cardiac Antiplatelets Clopidogrel CYP2C19 Efficacy Seizure Antiepileptics Carbamazepine HLA-B*1502 Toxicity Hepatitis C Antivirals Peginterferon alpha 2a Ribavirin IFNL3 HLA-B*44 Efficacy Sandburg J, Christal N, Marrazo J. Press Release - CVS Caremark; 2010. Available from: http://investor.cvs.com/phoenix.zhtml?c=99533&p=irol-newsArticle&id=1433463.
- 13. Integrating pharmacogenomics into your practice A step by step process
- 14. Patient Case Mr. Angina is a 63 y/o Caucasian male with a PMH of DM2, HTN, and HLD. He was recently diagnosed with a STEMI and underwent stent placement. Among several other medications, he was started on Clopidogrel. His PCP, Dr. Idunno, receives a phone call from ES about Clopidogrel pharmacogenomic testing. He doesn’t trust ES and hasn’t heard of this test before. He comes to you for help: Should he order this test? What should he do with the results?
- 15. Step 1 Check your pharmacogenomic resources to if there are genes related to the drug
- 17. CPIC Reviewed Drugs Clinical Pharmacogenetics Implementation Consortium (pharmgkb.org) Guidelines for HOW genetic tests should be used based upon peer reviewed evidence NOT focused on WHETHER to order the test. Assumption ->Preemptive genetic testing Published Guidelines Upcoming Publications Thiopurines Carbamazepine Clopidogrel Capecitabine Warfarin Phenytoin Codeine Rasburicase/Septra Abacavir Pegintron Simvastatin SSRIs Allopurinol Ivacaftor TCA’s Irinotecan
- 18. Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32.
- 19. Recommended Therapeutic use of Clopidogrel based on CYP2C19 genotype Likely Phenotype Genotype Implications for Clopidogrel Therapeutic Recommendations Classification of recommendations Ultrarapid Metabolizer (5-30%) CYP2C19: *1/*17 CYP2C19: *17/*17 Increased platelet inhibition Standard Clopidogrel dosing Strong Extensive Metabolizer (35-50%) CYP2C19: *1/*1 Normal platelet inhibition Standard Clopidogrel dosing Strong Intermediate Metabolizer (18-45%) CYP2C19: *1/*2 CYP2C19: *1/*3 CYP2C19: *2/*17 Reduced platelet inhibition = increased risk of CV events Alternative antiplatelet: Prasugrel or Ticagrelor* Moderate Poor Metabolizer (2-15%) CYP2C19: *2/*2 CYP2C19: *2/*3 Significantly reduced platelet inhibition = increased risk of CV events Alternative antiplatelet: Prasugrel or Ticagrelor* Strong * only if no contraindications to these alternatives Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32.
- 20. Step 2 Evaluate the pharmacogenomic test
- 21. General Considerations 1. Gene Association Positive Predictive Value (PPV) – percentage of patients who test positive for the allele and will be affected Negative Predictive Value – percentage of patients who test negative for the allele and will NOT be affected 2. Frequency Occurrence of variant gene in general population Often categorized by race/ethnicity 3. Clinical Utility What evidence exists to show that doing this test will improve patient outcomes?
- 22. Clopidogrel Patient Case 1. Gene Association – CYP2C19*2 carrier status PPV = % of patients with CYP2C19*2 who will have residual platelet aggregation (RPA) on clopidogrel PPV = 41.3% 22.4 % of patients with fully functional enzyme have RPA NPV = % of patients without CYP2C19*2 who will NOT have residual platelet aggregation NPV = 77.6% 2. Frequency 12% of Americans, 15% of Africans, and 29% of East Asians carry the CYP2C19*2 allele Ned Mmsc Phd RM. PLoS Curr. 2010;2:10.1371/currents.RRN1180. Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32.
- 23. 3. Clinical Utility No published RCT evaluating CYP2C19*2 testing utility Mayo Clinic TAILOR-PCI study – Enrolling patients to evaluate “bedside” CYP2C19*2 testing post PCI and impact on major adverse CV events Meta-analyses of Clopidogrel treated ACS patients undergoing PCI: Homozygous for CYP2C19*2 have an increased risk of adverse CV events (HR 1.76; 95% CI 1.24-2.50) and stent thrombosis (HR 3.97; 95% CI 1.75-9.02) compared to CYP2C19 full function homozygotes Clopidogrel Patient Case Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32. Roberts J, Wells G, May M, et. al. Lancet. 2012;379:1705-11. Pereira, N. TAILOR-PCI. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01742117
- 24. Step 3 Make your clinical decision
- 25. Clinical Decision For Mr. Angina, if ES is offering to coordinate test and is covered by insurance provider, do the test! Generally, consider performing the test in patients who have had an event while on Clopidogrel If preemptive testing were available, that would be ideal given events generally occur soon after PCI placement Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32.
- 26. Pharmacists in Pharmacogenomics Filling in the gap Opportunity to lead
- 27. St. Jude Pharmacist-Managed Pharmacogenetic Services Incorporated PGx services into PK services Gene Affected Formulary Drugs Effect of variant allele Thiopurine Methyltransferase (TPMT) 6-mercaptopurine Thioguanine Azathioprine Severe, sometimes fatal, hematological toxicity Cytochrome P450 2D6 (CYP2D6) Codeine Poor metabolizers = no analgesic effect Ultrarapid metabolizers = high toxicity risk Uridine glucouronosyltransferase 1A1 (UGT1A1) Irinotecan Increase potential for hematologic or GI toxicity Crews KR, Cross SJ, McCormick JN et al. Am J Health Syst Pharm. 2011;68(2):143-50
- 28. Patient EMR Crews KR, Cross SJ, McCormick JN et al. Am J Health Syst Pharm. 2011;68(2):143-50
- 29. St. Jude PG4KDS Program To test or not to test? Preemptively screen for 225 genes known to effect drug metabolism and place that information into the EMR Codeine (CYP2D6) and Azathioprine (TPMT) Pharmacists involved in continued evaluation of new research Erikson A. Pharmacy Today. American Pharmacists Association; 2013. Available from: http://www.pharmacist.com/pharmacogenetics-key-personalized-therapeutic-decisions
- 30. Take Home Pharmacogenomic testing can be useful Physicians are NOT using it because they lack knowledge Pharmacists need to become informed advocates
- 31. References 1. Crews KR, Cross SJ, McCormick JN et al. Development and implementation of a pharmacist-managed clinical pharmacogenetics service. Am J Health Syst Pharm. 2011;68(2):143-50. 2. Epstein RS, Moyer TP, Aubert RE et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (medco-mayo warfarin effectiveness study). J Am Coll Cardiol. 2010;55(25):2804-12. 3. Erikson A. Pharmacogenetics: The key to personalized therapeutic decisions. Washington, DC: American Pharmacists Association; 2013. Available from: http://www.pharmacist.com/pharmacogenetics-key-personalized- therapeutic-decisions. (Accessed 6/1/2013). 4. Express Scripts. Services: Personalized Medicine. Available at: http://www.express- scripts.com/services/physicians/personalizedmedicine/. Accessed 6/1, 2013. 5. Mallal S, Phillips E, Carosi G et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-79. 6. Moaddeb J, Haga SB. Pharmacogenetic testing: Current evidence of clinical utility. Therapeutic Advances in Drug Safety. 2013. 7. Ned Mmsc Phd RM. Genetic testing for CYP450 polymorphisms to predict response to clopidogrel: Current evidence and test availability. application: Pharmacogenomics. PLoS Curr. 2010;2:10.1371/currents.RRN1180.
- 32. References cont’d. 8. Pereira, N. Tailored Antiplatelet Therapy Following PCI (TAILOR-PCI). ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US) -2013. Available from: http://www.clinicaltrials.gov/ct2/show/NCT01742117 9. Relling MV, Klein TE. CPIC: Clinical pharmacogenetics implementation consortium of the pharmacogenomics research network. Clin Pharmacol Ther. 2011;89(3):464-7. 10. Roberts J, Wells G, May M, et. al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. 2012;379:1705-11. 11. Sandburg J, Christal N, Marrazo J. CVS caremark and generation health outline target medications that will be the focus of new pharmacogenomics partnership. Press Release. Online: CVS Caremark; 2010. Available from: http://investor.cvs.com/phoenix.zhtml?c=99533&p=irol-newsArticle&id=1433463. (Accessed 6/1/2013). 12. Scott SA, Sangkuhl K, Gardner EE et al. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther. 2011;90(2):328-32. 13. Simon T, Verstuyft C, Mary-Krause M et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360(4):363-75. 14. Stanek EJ, Sanders CL, Taber KA et al. Adoption of pharmacogenomic testing by US physicians: Results of a nationwide survey. Clin Pharmacol Ther. 2012;91(3):450-8.
- 33. Questions?
Editor's Notes
- Gauge audience: # students, # practicing pharmacists
- Today we are going to touch on 4 main things:Background/relevance Current stateStep-wiseImplementing pharmacist-run testing services
- DefinitionDetermines response, among other factorsResponse vs. ADR
- Why relevant to you?Growing field, evolving informationFDA modifications-example Warfarin genotype based dosingOf those changes 11% of them top 200 drugs, up from 1.5%Beyond it's growth, it is also shown improved outcomesWarfarin sensitivity related to genetics MMWES – pharmacogenomic testing decrease hosp d/t te and bleeding by 28-43%Another study - Abacavir an HIV drug is associated with a skin reaction that has a gene linked to it.Pharmacogenomic testing showed 100% reduction in confirmed reactions. Overall - growing field means you will encounter it in practice clinical utility – improve patient outcomes
- Now we know what it is and why it mattersLets talk about the current state and how often it is used.
- Study done by Medco/AMASurvey >10,000 physicians in 2008experience with pharmacogenomic testingLarge majority accept role >97%ONLY ~ 13% ordered a test in last 6 moLack of info @ testing30% had training in med school or after graduatingONLY 10 % felt informed @ testingTake away - Believe in impact, not testing, lack of knowledge
- Survey asked two groups of experts in the field:What major challenges to clinical implementation of pharmacogenomics?Largely corroborated previous surveyNew issue – cost and reimbursementNew test – not always covered by insuranceCost 1 test <$500
- Just a little joke to break up the presentationTime also a concern – specifically test turn-around timeTechnology has improved turn around timeMMWES was done took 32 days – 2008Depending on the test some are as quick as just 5h
- Generally we know now that testing is not being doneEffort to facilitate testing and decrease costs
- ES offered to physicians ID patients benefit testing based drug claimsexample, if you are prescribed Warfarin claim goes to ES- Call physician, ask if he want to testCoordinate testingPharmacists/Genetic counselors help to interpret resultsMake recs to physician
- CVS Caremark – similar service started 2010Similar medications, a few additional ones
- Talked about current stateKnow @ Lack of physician knowledgeKnow that PBMs are trying to facilitate testingInevitably this may lead increased testing and more physician questionsPharmacist should be a good resourceToday – step by step approach to a patient case
- Mr. AnginaPMH – DM2, HTN, HLDSTEMI with stent placementClopidogrelDr. Idunno call from ESDoesn’t trust themComes to you: Order the test? Results?
- One great resource: CPIC websiteGuidelines for genetic testing HOW to interpret resultsNOT whether to testPreemptive testing – talk about this later
- Go to websiteSearch for drugResultSummary of guidelines on webOR open guideline documentIF you have patient results – put them in & will tell you the guideline recommendation
- Stratify recommendations based genotype and phenotypeClopidogrel metabolized into active form by CYP2C19Active form inhibits platelet aggregationSome patients have variant alleles that cause them to be poor metabolizersDecreased platelet inhibition and increased CV riskChoose AltBEFORE use this, go to step 2
- Several considerations evaluatingGene association-PPV – have allele, are affected-NPV – don’t have allele, are not affectedFrequencyhow common is the allele in your patient?caution: low frequency, but severe reaction may still warrant testingClinical utility-Does this actually improve outcomes?
- Gene Association- Remember the positive gene result is for a non-functioning allele, so patients who are affected will have decreased clopidogrel functionPPV – relatively high compared to full function alleleThe negative gene result is for patients who DO NOT have the non-functioning allele, and DO NOT have decreased clopidogrel functionNPV high Frequency – low in Americans, but can go as high as 30% in east Asians and even higher in other populations.
- No published RCT showing that pharmacogenomic testing improves clinical outcomesMajor adverse CV events – non-fatal MI, non-fatal stroke, severe recurrent ischemia, CV death, and stent thrombosis.SummaryPatients with loss of function are at 2x risk of non-response to clopidogrelFrequency is moderatePatients with LOF are at increased risk of CV events and ST
- Talked about gap in physician knowledgeWalked through a practice caseHow to implement pharmacist-run pharmacogenomic programs
- St. Jude in 2005Pharmacists started PGx services into pharmacokinetic servicesMedication use record and screened most commonly used drugs with PGx clinical utility3 potetntial tests were found - TPMT, CYP2D6 and UGT1A1Pharmacists order and interpret tests and give recs to physicians
- Update EMRAvoid prescribing drugs that would be contraindicated with genotype
- 2011 St. Jude started a new programAvoid the decision to test, make more economically viablePreemptively screening children for genes affecting drug metabolismEnrolled over 1,000 patients so farCurrently ONLY using information for CYP2D6 and TPMTPharmacists directly involved in evaluating new research St. Jude is not the only one implementing preemptive testing, several funded research projects:University of Chicago has an ongoing clinical trial “The 1200 patients project”prospectively enrolling 1200 patients for preemptive screening and monitoring clinical decision supporteventual goal to look at patient outcomesUniversity of Florida and Stanford are also doing preemptive testing
- In conclusion…Testing NOT as often as thoughLack of knowlegde by physiciansPharmacists unique position to fill this gap