A presentation covering how far we have come with pharmacogenomic and how far we have to go. Background about what pharmacogenomics is and why it should matter to you is provided. Additionally, current physician and pharmacy benefit manager practices are covered. A step wise process for how to integrate pharmacogenomics into your practice is included. And lastly, examples of pharmacists using pharmacogenomics in their practice is provided.
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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
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.
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
16.
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.
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
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.
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.
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