The Current State of

Pharmacogenomics

Marti LarrivaPharmD Candidate, Class of 2014

University of Arizona

ObjectivesDiscuss 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

BackgroundPharmacogenomics

Relevance

PharmacogenomicsDefinition: The genetic influence of your response

to drugs

RelevanceFDA pharmacogenetic modifications to >100 drug labels

Of top 200 drugs2003 – 1.5%

2011 – 11%

Mayo-Medco Warfarin Effectiveness Study28-43% 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.

Current State of Pharmacogenomics

How often is it being used?

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Stanek EJ, Sanders CL, Taber KA et al. Clin Pharmacol Ther. 2012;91(3):450-8.

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 ConsortiumASCPT = American Society for Clinical Pharmacology and Therapeutics

Relling MV, Klein TE. Clin Pharmacol Ther. 2011;89(3):464-7.

PBM Facilitated Pharmacogenomic

TestingPBMs = Pharmacy Benefits Managers =

process prescriptions for groups that pay for drugs

(insurance companies or corporations)

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

ImatinibNilotinibDasatinib

BCR/ABL Efficacy

Cardiac Vitamin K antagonist

Warfarin CYP2C9VKORC1

Toxicity

Antiplatelet Clopidogrel CYP2C19 Efficacy

CVS CaremarkUse Class Drug Gene Concer

n

HIV Antiretrovirals Abacavir HLA-B*5701

Toxicity

Cancer Thiopurines AzathioprineThioguanine

TPMT Efficacy

Anti-estrogens Tamoxifen CYP2D6 Efficacy

Protein kinase inhibitor

ImatinibNilotinibDasatinibErlotinibLapatinib

BCR/ABL Efficacy

Cardiac Antiplatelets Clopidogrel CYP2C19 Efficacy

Seizure Antiepileptics Carbamazepine HLA-B*1502

Toxicity

Hepatitis C

Antivirals Peginterferon alpha 2aRibavirin

IFNL3HLA-B*44

EfficacySandburg 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.

Integrating pharmacogenomics into your practice

A step by step process

Patient CaseMr. 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?

Step 1Check your pharmacogenomic resources to if there are genes related to the drug

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

Scott SA, Sangkuhl K, Gardner EE et al. Clin Pharmacol Ther. 2011;90(2):328-32.

Recommended Therapeutic use of Clopidogrel based on

CYP2C19 genotypeLikely Phenotype

Genotype Implications for Clopidogrel

Therapeutic Recommendations

Classification of recommendations

Ultrarapid Metabolizer(5-30%)

CYP2C19: *1/*17CYP2C19: *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/*2CYP2C19: *1/*3CYP2C19: *2/*17

Reduced platelet inhibition = increased risk of CV events

Alternative antiplatelet: Prasugrel or Ticagrelor*

Moderate

Poor Metabolizer(2-15%)

CYP2C19: *2/*2CYP2C19: *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.

Step 2Evaluate the pharmacogenomic test

General Considerations1. 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?

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.

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

Step 3Make your clinical decision

Clinical DecisionFor 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.

Pharmacists in Pharmacogenomics

Filling in the gapOpportunity to lead

St. Jude Pharmacist-Managed

Pharmacogenetic ServicesIncorporated PGx services into PK services

Gene Affected Formulary Drugs

Effect of variant allele

Thiopurine Methyltransferase (TPMT)

6-mercaptopurineThioguanineAzathioprine

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

Patient EMR

Crews KR, Cross SJ, McCormick JN et al. Am J Health Syst Pharm. 2011;68(2):143-50

St. JudePG4KDS ProgramTo 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

Take HomePharmacogenomic testing can be useful

Physicians are NOT using it because they lack knowledge

Pharmacists need to become informed advocates

References1. 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.

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.

Questions?