1. Pharmacogenomics: Genetic Factors Influencing Drug Response
Angela S. Stewart, Pharm.D., BCPS
Clinical Associate Professor
Assistant Dean – Yakima Extension
College of Pharmacy
Washington State University

2. JB is a 63 year old Caucasian gentleman with newly diagnosed atrial fibrillation who needs to be started on warfarin therapy for stroke prevention. He is 5’10”, 187 #, SrCr 1.3, H/H 13.9/42. He has DMII, hyperlipidemia, and HTN controlled on metformin, lisinopril, and rosuvastatin. He is a non-smoker and social drinker. What initial warfarin dose would you select?
Patient Case

3. JB is a 63 year old Caucasian gentleman with newly diagnosed atrial fibrillation who needs to be started on warfarin therapy for stroke prevention. He is 5’10”, 187 #, SrCr 1.3, H/H 13.9/42. He has DMII, hyperlipidemia, and HTN controlled on metformin, lisinopril, and rosuvastatin. He is a non-smoker and social drinker. What initial warfarin dose would you select? What follow-up and monitoring will you order?
Patient Case

4. JB is a 63 year old Caucasian gentleman with newly diagnosed atrial fibrillation who needs to be started on warfarin therapy for stroke prevention. He is 5’10”, 187 #, SrCr 1.3, H/H 13.9/42. He has DMII, hyperlipidemia, and HTN controlled on metformin, lisinopril, and rosuvastatin. He is a non-smoker and social drinker. The patient returns 3 days later and is complaining of bleeding gums, increased bruising, and his INR is 6.5. He is instructed to hold warfarin and return to clinic in 2 days for another INR check. Can genetics help to explain this patients sensitivity to warfarin?
Patient Case

5. State a rationale for advancing a personalized medicine approach in your practice
Define pharmacogenomics
Review basics of pharmacokinetics and genetics as they relate to pharmacogenomics
List common examples of genetic polymorphisms that may alter response to medications
Identify tools and resources useful in applying genetic information to patient care
Apply genetic testing information in medical decision making for common clinical scenarios
Recognize barriers to incorporation of pharmacogenomics information into practice
Objectives:

6. Outline Genomics Definitions Genetics Review
Genetic Variation & Pharmacokinetics vs Pharmacodynamics
Tools and Resources
Clinically Relevant Examples
Outline

7. Personalized Medicine
AKA: genomic medicine, precision medicine
Wikipedia Definition: medical care that separates patients into different groups – with medical decisions, practices, interventions, and/or products being tailored to the individual patient based on their predicted response or risk of disease.
PERSONALIZED MEDICINE CAN: • Shift the emphasis in medicine from reaction to prevention • Direct the selection of optimal therapy and reduce trial-and-error prescribing • Help avoid adverse drug reactions • Increase patient adherence to treatment • Improve quality of life • Reveal additional or alternative uses for medicines and drug candidates • Help control the overall cost of health care
Personalized Medicine

8. Clin Infect Dis November 15, 2005 vol. 41 no. Supplement 7 S449-S452

9. The study of how genes affect a person's response to drugs
The study of how genes affect a person's response to drugs. This relatively new field combines pharmacology (the science of drugs) and genomics (the study of genes and their functions) to develop effective, safe medications and doses that will be tailored to a person's genetic makeup.
Pharmacogenetics - Study of variability in drug response determined by single genes.
Pharmacogenomics - Study of variability in drug response determined by multiple genes within the genome.
Pharmaco- Genomics

10. DNA Double Helix

11. Transcription and Translation

12. Gene Expression

13. Mendellian Inheritance

14. Common Genetic Variation
Single Nucleotide Polymorphisms (SNPs)
Copy Number Variants (CNV)
Insertions/Deletions (Indels)
Variable Number Tandem Repeats (VNTR)
Common Genetic Variation

15. SNP

16. Genotype & Phenotype

17. Kinetics & Dynamics

18. Absorption Distribution Excretion
Genetic Variability in Drug Transporter Proteins
ABCB1 gene – p-Glycoprotein, multi-drug resistance 1
ABCG2 – breast cancer resistance protein
OATP – organic anion transporter proteins
Absorption Distribution Excretion

19. Drug Metabolism Phase I Functionalization Reactions
Oxidation
Reduction
Cytochrome P450 Enzyme Systems
Phase II Conjugation Reactions
Glucuronidation
Sulfation
Others
Drug Metabolism

20. Variability in CYP enzymes

21. Variabililty in Phase II Enzymes
N-acetyltransferase (NAT2)
Cancer risk
Metabolism of isoniazide, caffeine, others
UDP-glucuronosyltransferase (UGT1A1*28)
Gilbert’s Syndrome
Metabolism of irinotecan
Thiopurine methyltranferase (TPMT)
Metabolism of 6-mercaptopurine and azathioprine
Variabililty in Phase II Enzymes

22. Clinically Relevant Examples
Disease
Drug Example
DME &
variant alleles
Depression
Tricyclic Antidepressants
CYP2D6*3,*4,*6
CYP2C19*2, *3, *17
Thromboembolic Disorders
Warfarin
Clopidogrel
CYP2C9*2, *3
GI Diseases
Proton Pump Inhibitors
CYP2C19*2, *3
Pain Management
Codeine
CYP2D6*4, *5, *6
Malignant Diseases
Thiopurines
Irinotecan
TPMT *2, *3A, *3C
UGT1A1 *28, *6, *27
Clinically Relevant Examples

23. Pharmaco-dynamics Genetic Variability Affecting Drug Targets
VKOR – Vitamin K Epoxide Reductase
ACE – Angiotensin I Converting Enzyme
ADRB2 – Beta 2 Receptor
Pharmaco-dynamics

24. JB is a 63 year old Caucasian gentleman with newly diagnosed atrial fibrillation who needs to be started on warfarin therapy for stroke prevention. He is 5’10”, 187 #, SrCr 1.3, H/H 13.9/42. He has DMII, hyperlipidemia, and HTN controlled on metformin, lisinopril, and rosuvastatin. He is a non-smoker and social drinker. The patient returns 3 days later and is complaining of bleeding gums, increased bruising, and his INR is 6.5. He is instructed to hold warfarin and return to clinic in 2 days for another INR check. Which available genetifc test(s) may explain this patient’s sensitivity to warfarin?
Patient Case

25. Metabolism and therapeutic action of warfarin.
Qiang Ma, and Anthony Y. H. Lu Pharmacol Rev 2011;63:
U.S. Government work not protected by U.S. copyright

26. Warfarin Gene/Allele of Interest Functional Effect
CYP2C9 *2 or *3
VKORC1 (-1639G>A)
Functional Effect
Reduced metabolism of S-warfarin
Reduced expression of VKOR protein
Population Prevalence
CYP2C9*2 an *3 = 5% each
VKORC1 variant 36%, 88% East Asians
Clinical Significance
Together account for approximately 40% of variability in response
Contribute to increased warfarin sensitivity
Warfarin

27. JB is a 63 year old Caucasian gentleman with newly diagnosed atrial fibrillation who needs to be started on warfarin therapy for stroke prevention. He is 5’10”, 187 #, SrCr 1.3, H/H 13.9/42. He has DMII, hyperlipidemia, and HTN controlled on metformin, lisinopril, and rosuvastatin. He is a non-smoker and social drinker. The results of JB’s genomic testing reveal that he has the VKORC1 AA genotype and is an CYP2C9 *1/*2 genotype (intermediate metabolizer phenotype). How will you use this information to personalize his drug therapy?
Patient Case

28. Warfarin Dosing with Genotyping
Warfarin Dose (mg/day)
Coumadin package insert

29. Genomic Dosing for Warfarin
Package Insert – genotype information, when available, can assist in selecting the starting dose
CPIC – use warfarin dosing algorithm that incorporates genetic information
Conflicting results in clinical trials
N Engl J Med 2013; 369:
N Engl J Med 2013; 369:
Genomic Dosing for Warfarin

30. Clinically Useful Websites
CPIC – Clinical Pharmacogenetics Implementation Consortium
Clinical guidelines for use of genomic testing/dosing
guidelines.do?source=CPIC
Food and Drug Administration (FDA)
Drugs with genomic information in package insert
armacogenetics/default.htm
WarfarinDosing.org
Free website and genomic dosing calculator
National Human Genome Research Institute
NIH Institute dedicated to advancing application ofgenomics research
Genetics Home Reference
Consumer-friendly information on the effects of genetic variation on human health.
Clinically Useful Websites

31. Commercially Available Tests
Genetic Testing Registry (GTR)
Central location for information on available tests
Examples from GTR
Genelex and YouScript Decision Support
61 conditions/phenotypes in 29 tests
MD Labs and RxIGHT Pharmacogenetics
79 conditions/phenotypes in one test
OneOME
94 conditions/phenotypes in one test
Direct to Consumer Testing Information
International Society of Genetic Geneology Wiki
ompanies
Commercially Available Tests

32. Barriers to Full Implementation
Practical issues involved in clinical implementation of pharmacogenomic testing in healthcare system.
Issue
Challenge
Test performance
Reasonable turnaround time for delivery of test result
Interpretation of result
Not a straightforward normal versus abnormal interpretation Education of clinicians is crucial to proper use
Education of health professionals
Variable time and content devoted to educating future clinicians within health professional schools Overwhelming information for most current practicing clinicians
Cost reimbursement by payers
Almost exclusively based on proof of cost-effectiveness
Acceptance by clinicians
Potential additional workload Potential legal liability Health disparity concern for patient
Acceptance by patients
Privacy and discrimination concern Health disparity concern Ownership of genetic information
Barriers to Full Implementation

33. Clopidogrel CYP2C19 Prevalence Effect Recommendation
Ultra-rapid metabolizer
*1/*17
*17/*17
5-30%
Increased platelet inhibition
Monitor for increased bleeding
Extensive metabolizer
*1/*1
35-50%
Normal platelet inhibition
Normal dosing
Intermediate metabolizer
*1/*2
*1/*3
*2/*17
18-45%
Reduced platelet inhibition, increased risk for CV events
Consider alternative anti-platelet agents
Poor metabolizer
*2/*2
*2/*3
*3/*3
2-15%
Significantly reduced platelet inhibition, increased risk for CV events
Use alternative anti-platelet agents
Clopidogrel

34. Phenotype
CYP2D6
Prevalence
CYP2C19
Poor metabolizer
*3/*4
*4/*4
*5/*5
1-10%
*2/*2
*2/*3
*3/*3
2-15%
Normal Metabolizer
*1/*1
72-88%
34-50%
Ultra-rapid metabolizer
*1/*1xN
1-20%
*17/*17
2-5%
Amitriptylline
PM’s – greatly reduced metabolism, increased risk for ADR’s, consider alternative agents or at least 50% dose reduction
URM’s – increased metabolism to less active compounds, lower plasma concentrations, increased risk for treatment failure, consider alternative agents

35. Codeine Metabolism Phenotype Allele Prevalence Effect Recommendation
Ultra-rapid
*1/*1N
*1/*2N
1-2%
Increased formation of morphine
Avoid use due to toxicity
Extensive
*1/*1
*1/*2
*2/*2
77-92%
Normal formation of morphine
Normal dosing
Intermediate
*4/*10
*5/*41
2-11%
Reduced formation of morphine
Normal dosing, monitor for response
Poor
*4/*4 *4/*5 *5/*5
5-10%
Greatly reduced formation of morphine
Avoid use due to lack of efficacy
Codeine

36. Personalized Medicine and Pharmacogenomcis may improve patient outcomes
There are a wide variety of genetic polymorphisms that may alter an individuals response to medications
Genetic testing is becoming more widely available and affordable
Guidelines exist to help in utilizing genetic information to optimize drug therapy
Barriers still exist to full incorporation of pharmacogenomic information into routine medical decision making
Conclusions