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Pharmacogenomics in Community Pharmacy Practice: A Look into the Future of Personalized Medicine

Pharmacogenomics in Community Pharmacy Practice: A Look into the Future of Personalized Medicine. A.J. Greco, PharmD PGY2 Community Pharmacy Resident UNC Eshelman School of Pharmacy Kerr Drug May 15, 2012. Disclosures.

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Pharmacogenomics in Community Pharmacy Practice: A Look into the Future of Personalized Medicine

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  1. Pharmacogenomics in Community Pharmacy Practice: A Look into the Future of Personalized Medicine A.J. Greco, PharmD PGY2 Community Pharmacy Resident UNC Eshelman School of Pharmacy Kerr Drug May 15, 2012

  2. Disclosures • I have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. • A grant from the Community Pharmacy Foundation has been received for research support for the community pharmacy project entitled Implementation of a Personalized Medicine (Pharmacogenomics) Service in a Community Pharmacy.

  3. Objectives • Define basic pharmacogenomic terms, concepts, and nomenclature • Describe genetic polymorphisms and their effects on pharmacokinetics and pharmacodynamics • Identify how pharmacogenomic testing can be applied to clinical pharmacy practice, using clopidogrel and warfarin as examples • Given a patient case, formulate an evidence-based recommendation using the results of pharmacogenomic testing • Discuss the role of pharmacogenomics in community pharmacy practice

  4. Personalized Medicine • Imagine: • Being able to find out how a drug will affect you before you take it • Receiving a medication that is specifically tailored to treat your disease • Personalized Medicine is the use of knowledge about an individual patient’s genetic make-up to influence the drugs and doses chosen for a patient.

  5. Pharmacogenomics • Study of how genetic differences in MULTIPLE genes influence variability in drug response (i.e., efficacy and toxicity) • Patients experiencing great variations in drug response despite receiving a fixed dose • Completion of human genome project in 2003 allowed concept to become more tangible Pharmacy Today. 2009;15(12):36-48.

  6. Let’s Travel Back in Time

  7. A Not So New Concept • 1866 – Gregor Mendol establishes rules of heredity • 1913 – William Bateson introduces the term genetics • 1959 – Vogel coins the term pharmacogenetics • 1967 – Sjoqvist establishes that metabolism of TCAs is under genetic control • 1987 – First nomenclature of the P450 supergene family • 2003 – Human genome project is complete Nature Reviews Genetics. 2004;5:669-676.

  8. Molecular Biology 101 • A chromosome is the structural component of DNA that resides in the cell nucleus • Carries all of the genetic material • Humans possess a total of 46 chromosomes (or 23 pairs) • Each chromosome contains a single DNA molecule Pharmacy Today. 2009;15(12):36-48.

  9. Molecular Biology 101 • DNA is the double-helix molecule , and segments or regions of DNA are known as genes • Genes contain nucleotide sequences needed for messenger ribonucleic acid (mRNA) transcription • Four nucleotide bases exist in DNA

  10. Molecular Biology 101 • DNA building blocks = 4 nucleotide bases • Purine Bases • Adenine (A) • Guanine (G) • Pyrimidine Bases • Thymine (T) • Cytosine (C) Pharmacy Today. 2009;15(12):36-48.

  11. Molecular Biology 101 • Complementary base pair formation occurs when an A pairs with a T or when a G pairs with a C • A T • G C • Arrangement of base pairs provides the DNA sequence by which amino acids are determined • Results in protein synthesis Pharmacy Today. 2009;15(12):36-48.

  12. Polymorphisms • Polymorphism = variation in the DNA sequence present in more than 1% of the population • Single nucleotide polymorphism (SNP; pronounced “snip”) = a type of polymorphism for which variation occurs in a single nucleotide base • Other polymorphisms include large segments of the DNA sequence that consist of a specific gene or numerous genes • i.e. Gene deletion polymorphism Pharmacy Today. 2009;15(12):36-48.

  13. SNP Nomenclature • A SNP can be described in a numeric and alphabetic context • Provides information regarding: • Specific gene • Location of the SNP with respect to the gene • Nucleotides involved Pharmacy Today. 2009;15(12):36-48

  14. SNP Nomenclature ABCB1 3435 C > T • Gene = First few letters/numbers • Location on DNA (SNP location) = Numbers between gene name and the nucleotide • First nucleotide letter = original nucleotide (reference nucleotide) • Second nucleotide letter = nucleotide change (variant nucleotide) Pharmacy Today. 2009;15(12):36-48.

  15. Now You Name that SNP! An example of a SNP is the VKORC1 1173 C>T. Based on the pharmacogenomic nomenclature of this SNP, what is the gene of interest? • 1173 • VKORC1 • VKORC1 1173 • VKORC1 C>T

  16. Alleles • Allele = one of the variant forms of a gene at a particular location on a chromosome • Humans possess two alleles • One allele acquired from your biological mother • The other from your biological father • Different allele subtypes can exist for a gene Pharmacy Today. 2009;15(12):36-48.

  17. Allele Subtypes • Cytochrome P450 (CYP) gene CYP2C19 • Examples of three allele subtypes: • CYP2C19*1 • CYP2C19*2 • CYP2C19*3 • CYP2C19 = gene • *1, *2, *3 = allele subtype

  18. Allele Subtypes • Identifying subtypes is relevant to the functional effect for each gene Pharmacy Today. 2009;15(12):36-48.

  19. Homozygous vs. Heterozygous • An individual genotype identifies both alleles for a specific gene • If both alleles in an individual are CYP2C19*2, the respective genotype would be homozygous and identified as: • CYP2C19*2/*2 • If an individual has one CYP2C19*2 allele and one CYP2C19*3 allele, then the respective genotype would be heterozygous and identified as: • CYP2C19*2/*3

  20. Now You Determine Enzyme Activity! • A physician orders genetic testing for his patient with the following result: CYP2C19*2/*3 • Which of the following is correct regarding enzyme activity? • The patient’s genotype is homozygous with normal functional activity • The patient’s genotype is heterozygous with normal functional activity • The patient’s genotype is homozygous with a loss-of-functional activity • The patient’s genotype is heterozygous with a loss-of- functional activity

  21. Effects on Pharmacokinetics and Pharmacodynamics PharmGKB (www.pharmgkb.org)

  22. Let’s Travel Back to the Future

  23. Plavix (clopidogrel) and Pharmacogenomics PharmGKB (www.pharmgkb.org) accessed 10-23-11

  24. Plavix (clopidogrel) and Pharmacogenomics Plavix [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2011.

  25. Cytochrome P450 Polymorphisms and Response to Clopidogrel N Engl J Med. 2009;360:354-62.

  26. Cytochrome P450 Polymorphisms and Response to Clopidogrel N Engl J Med. 2009;360:354-62

  27. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention Eur Heart J. 2009; 30:916-22.

  28. Plavix (clopidogrel) Genetic Testing Recommendations • Tests are available to identify a patient's CYP2C19 genotype • These tests can be used as an aid in determining therapeutic strategy • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers Plavix [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2011

  29. CYP2C19 Genotype/Phenotype • Extensive metabolizer • Normal activity • *1/*1 • Ultra-rapid metabolizer • Normal or increased activity • *1/*17, *17/*17 • Intermediate metabolizer • Intermediate activity • *1/*2, *1/*3 • Poor metabolizer • Low or deficient activity • *2/*2, *2/*3

  30. Treatment Recommendations • Clopidogrel label-recommended dosage and administration • *1/*1 • Clopidogrel label-recommended dosage and administration • *1/*17, *17/*17 • Prasugrel or other alternative therapy (if no contraindications) • *1/*2, *1/*3 • Prasugrel or other alternative therapy (if no contraindications) • *2/*2, *2/*3

  31. Patient Case • A.G. is a 51 year old caucasian male with hypertension and dyslipidemia who suffers a non-ST-elevated myocardial infarction • He undergoes percutaneous coronary intervention (PCI) with placement of 2 drug-eluting stents • Patient weighs 90 kg, NKDA • Genotype: CYP2C19*2/*2 • He is started on clopidogrel 300 mg loading dose, followed by 75 mg/day maintenance dose

  32. Patient Case Based on A.G.’s genotype, what is your recommendation? • No change in therapy • Continue clopidogrel 75 mg daily with increased monitoring for risk of bleeding C. Increase clopidogrel to 75 mg twice daily (150 mg total daily dose) D. Change to alternative therapy such as Effient (prasugrel) 10 mg daily

  33. Warfarin and Pharmacogenomics Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011.

  34. Warfarin and Pharmacogenomics http://www.mayomedicallaboratories.com .

  35. Warfarin and Pharmacogenomics Variability in Warfarin Drug Response Liver function Foods Other Drugs Age Body Size Gender Ethnicity Genetics Warfarin Drug Response

  36. Warfarin and Pharmacogenomics Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011.

  37. Warfarin and Pharmacogenomics • Decreased CYP2C9 enzyme activity results in increased S-warfarin concentrations • Predisposes the patient to increased risk of bleeding Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011

  38. Warfarin and Pharmacogenomics VKORC1 1639 G > A • Individuals with an A allele produce less VKORC1 than do those with the G allele • Lower warfarin doses are needed to inhibit VKORC1 and to produce an anticoagulant effect in carriers of the A allele

  39. Warfarin Genetic Testing Recommendations • Pharmacogenomic testing for CYP2C9 and VKORC1 polymorphisms may improve prediction of warfarin target maintenance doses • Testing may decrease: • Time to stabilization of warfarin dose • Risk of above-average INRs • Risk of serious bleeding events

  40. Warfarin Genetic Testing Recommendations • Currently, testing for CYP2C9 and VKORC1 is not required • Health providers should not delay initiation of warfarin therapy for genetic testing • Genetic testing is not appropriate for patients already on warfarin • Genetic testing does not replace INR monitoring Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011.

  41. Warfarin Genetic Testing Recommendations • Dosing nomograms based on genotype are suggested by the manufacturer Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011.

  42. Patient Case • R.S. is a 58 year old caucasian male with newly diagnosed atrial fibrillation. He is to be initiated on warfarin therapy. • He is 5’8’’ and weighs 165 lbs • NKDA • Not currently receiving other meds that would interact with warfarin • Genetic testing is ordered and the results are: • CYP2C9*2/*3 • VKORC1 AG

  43. Patient Case • What dose range of warfarin would you recommend for this patient based on the information given? • 0.5 – 2 mg • 3 - 4 mg • 5 – 7 mg • 7.5 – 10 mg

  44. Warfarin Genetic Testing Recommendations • Dosing nomograms based on genotype are suggested by the manufacturer Warfarin [package insert]. Princeton, NJ: Bristol-Myers Squibb Pharma Company; 2011.

  45. Pharmacogenomics in Community Pharmacy • Pharmacists practicing in community pharmacy routinely optimize drug therapy through medication therapy management (MTM) • Patient-specific information is used to generate a clinical recommendation and determine the most appropriate medication regimen J Am Pharm Assoc. 2011;51:189-193

  46. Pharmacogenomics in Community Pharmacy • Community pharmacists also routinely perform point of care (POC) services: • Full-lipid panels • Blood glucose monitoring • Hemoglobin A1C • Bone mineral density screening J Am Pharm Assoc. 2011;51:189-193.

  47. Pharmacogenomics in Community Pharmacy • As medication experts and POC service providers pharmacists can: • Educate physicians and patients • Perform the actual sample collection to be utilized for genetic testing • Community pharmacy can serve as an easily accessible healthcare setting J Am Pharm Assoc. 2011;51:189-193.

  48. Pharmacogenomics in Community Pharmacy • Pharmacogenomics can actually be integrated into currently offered services • Let’s look at an example: • A pharmacogenomic application can easily be identified during a comprehensive medication review (CMR) • Pharmacist performing the CMR may identify that the patient is on Plavix (clopidogrel) • Explain the importance of pharmacogenomics testing and offer this service J Am Pharm Assoc. 2011;51:189-193.

  49. Pharmacogenomics in Community Pharmacy • Pharmacist can perform a buccal swab in minutes • Send the collected DNA to the lab • Interpret results and discuss with physician • Contact the patient to explain the results and any changes in therapy Say Ahhhhh….. J Am Pharm Assoc. 2011;51:189-193.

  50. Pharmacogenomics in Community Pharmacy • Numerous barriers must first be overcome if this model can truly work in community pharmacy • Barriers include: • Knowledge regarding pharmacogenomics • Ability to order or interpret pharmacogenomic lab tests • Determining and billing payers • Defining the return on investment • Patient and prescriber acceptance • Time J Am Pharm Assoc. 2011;51:189-193.

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