1. Precision Healthcare: Pharmacogenomics & Pain Management
Mitchell Knisely, PhD, RN-BC, ACNS-BC
Postdoctoral Scholar
University of Pittsburgh School of Nursing
February 7, 2017

2. Overview of Presentation
Advances in Genomic Science
Foundations of Pharmacogenomics & Translation to Practice
Pharmacogenomics & Pain Management
Cytochrome P450 Drug Interactions
Implications for Practice

3. (National Pain Strategy, 2016)
“Evidence suggests that wide variations in clinical practice and inadequate tailoring of pain therapies to individuals...not only contribute to poor quality of care for people with pain, but also increase health care costs.”
(National Pain Strategy, 2016)

4. Advances in Genomic Science

5. “…the most important, most wondrous map ever produced by humankind.”
Human Genome Project
World-wide research effort
Goal of analyzing the structure of human DNA and determining the location of human genes
Draft of the human genome was announced in June and published in February 2001
“…the most important, most wondrous map ever produced by humankind.”
– President Clinton

6. Benefits of Human Genome Project
Molecular Medicine
Improve diagnosis of disease
Create drugs based on molecular information
Microbial Genomics
Rapidly detect & treat pathogens in clinical practice
Risk Assessment
Evaluate health risks faced by individuals who are exposed to certain environmental conditions
DNA Identification (Forensics)
Match potential suspects with DNA evidence left at crime scene

7. Post-Human Genome Project Era 2003 - present
Collins et al. Nature. 2003;422(6934):
The International Genome Sample Resource:

8. Genetic Information Nondiscrimination Act (GINA)
Provides minimum protection against genetic discrimination.
2 main protections:
Total restriction on the use of genetic health information to make employment decisions.
Prohibition on making genetic information a requirement for attaining health insurance.

9. Precision Medicine Initiative ®
Announced by President Obama at State of the Union Address.
The Precision Medicine Initiative® will generate the scientific evidence needed to move the concept of precision medicine into clinical practice.
Precision medicine (health): an emerging approach for disease prevention and treatment that takes into account people’s individual variations in genes, environment, and lifestyle.

10. Precision Health & Pharmacogenomics
Identify genetic or protein biomarkers to predict drug response and side effects.
Identifying the right drug, for the right patient, at the right time, at the most optimal dose.

11. Foundations of Pharmacogenomics & Translation to Clinical Practice

12. “Current” Medical Paradigm
“One-size-fits all approach”

13. What is Pharmacogenomics?
Study of genomic variations associated with drug response.
Understand how genetic variation contributes to variability in drug disposition, response, & toxicity.

14. Pharmacogenomics in Practice
65-90% of adult patients is prescribed 1 or more pharmacogenetically actionable variants.
Lack of efficacy and adverse drug effects r/t interpatient variability = poor patient outcomes and increased healthcare costs
Pharmacogenomic information is clinically actionable – not necessarily “stigmatizing.”

15. What are genetic variations?
A genetic variant is a difference in the DNA sequence compared with a reference sequence.
Polymorphism: A genetic variant that is common (≥ 1% in the population).
Mutation: A genetic variant that is rare (< 1% in the population.
Allele: one of two or more versions of a gene.
Most common type of genetic variation is a single nucleotide polymorphism (SNP).
SNPs can alter a person’s ability to metabolize certain drugs.

16. Factors Affecting Pharmacokinetics & Pharmacodynamics of Drugs
Prescribed dosing regimen
Drug at site of action
Drug
effects
Compliance
Dosing & medication errors
Absorption
Tissue & body fluid mass & volume
Drug interactions
Elimination
Drug metabolism
Drug receptor status
Genetic factors
Drug interactions
Tolerance
Spruill et al. (2014). Clinical Pharmacokinetics. Bethesda, MD: ASHP.

17. Pharmacogenetic Classification of Genes
Drug-transporter pharmacogenetics:
Genes that code for membrane transporters that move drugs either into or out of cells.
Drug-target pharmacogenetics:
Genes that code for the direct target of the drug.

18. Pharmacogenetic Classification of Genes
Drug-metabolizing pharmacogenetics:
Includes variations in genes that are involved in the metabolism of the drug.
Genes include those that code for metabolizing enzymes that may either:
Activate an inactive PRODRUG into an active agent; or
Inactivate an ACTIVE DRUG to an inactive metabolite.

19. Genetic Variants’ Clinical Impact on Drug Metabolism
Gain-of-function Mutation
Wild Type Allele
Loss-of-Function Mutation
↑ drug-metabolizing enzyme activity
Normal drug-metabolizing enzyme activity
No or ↓ drug-metabolizing enzyme activity
Active Drug
Little or No Active Drug
Appropriate
Dose
↑ Active Drug Exposure
Pro Drug
Brazeau, D. (2015). Basics of pharmacogenomics. In D. Lea, D. Cheek, D. Brazeau, & G. Brazeau (eds.), Mastering Pharmacogenomics. Indianapolis, IN: STTI.

20. Drug Metabolizing Phenotypes
Clinical Interpretation
Ultra-rapid metabolizers (UM)
Increased risk for toxicity
Extensive metabolizers (EM)
Should be able to achieve therapeutic effects with normal dosing
Intermediate metabolizers (IM)
May show reduced effects with normal dosing
Poor metabolizers (PM)
Lack of therapeutic effects may be observed

21. Translating Pharmacogenetic Testing to Clinical Practice
Mitigate/Cure
Pharmacogenetic Test
Administer drug
TAGCTGCTGC
Genotype
Phenotype
Select alternative drug/adjust dosing
TAACTGCTGC
Adverse drug effect

22. Pharmacogenomic Practice Resources
U.S. Food & Drug Administration (FDA):
> 170 drugs have pharmacogenomic information on drug labels.
Source:

23. Pharmacogenomic Practice Resources
PharmGKB:

24. Pharmacogenomic Practice Resources
Clinical PGx Implementation Consortium (CPIC):
CPIC guidelines help clinicians understand HOW available genetic test results should be used to optimize drug therapy.
Not WHETHER tests should be ordered.
36 medications with CPIC Guidelines
Additional guidelines from the Dutch Working Group & other professional organizations.

25. Elements of CPIC Guidelines
Introduction
Focused Literature Review
Gene:
Background
Genetic Test Interpretation
Available Genetic Test Options
Incidental findings
Other considerations
Drug(s):
Linking genetic variability to variability in drug-related phenotypes
Dosage Recommendations
Table 2. Recommended Dosing of ____ [drug/s] by ____ [gene] phenotype
Strength of recommendations grading system
Recommendations for Incidental Findings
Potential Benefits and Risks for the Patient
Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests
Source:

26. Pharmacogenomic Practice Resources
NCBI – Genetic Testing Registry (GTR):
Access to other resources on NCBI:

27. Pharmacogenomics & Pain Management

28. Benefits of Pharmacogenomics in Pain Management
Improved drug safety.
Ability to optimize individual therapies.

29. Drug Safety - Codeine

30. Genomic Background of Pain Management
Functional Pain Genomics
Genetic variants modulating risks of:
Pain disease development
Clinical course
Severity
Pharmacogenomics of Pain Mgmt.
Genetic variants influencing:
Pharmacokinetics
Pharmacodynamics
Analgesic response/outcome
Janicki, P. (2013). Comprehensive Treatment of Chronic Pain by Medical, Interventional Approaches.

31. Genetic Factors Influencing Analgesic Response
Pharmacokinetic Factors
Pharmacodynamic Factors
Drug-metabolizing enzymes
Drug receptors
CYP2D6, CYP3A4
OPRM1, OPRK1
Drug elimination
Signal transduction
UGT2B7
COMT, STAT6
Drug transporters
ABCB1, MDR1

32. Opioid Signaling Pathway
Laugsand et al. European Journal of Cancer. 2011;47:

33. Well-Known Pharmacogenomic Associations: Analgesics
Genes
Dosing Guideline
Acetaminophen
CYP1A2, CYP2D6, CYP2E1, CYP3A4
None
Celecoxib
CYP2C9, CYP2D6
Codeine*
CYP2D6, CYP3A4, UGT2B4, UGT2B7
CPIC, DPWG, PRO
Fentanyl
CYP3A4
Oxycodone
CYP2D6
DPWG
Tramadol*
Legend:
* = PGx Info on FDA label
CPIC: Clinical Pharmacogenetics Implementation Consortium
DPWG: Royal Dutch Assoc. for the Advancement of Pharmacy – PGx Working Group
PRO: other professional society

34. Pharmacogenomic Associations: Analgesics
Genes
Morphine
UGT2B7, ABCB1, COMT, OPRM1, CGH1
Hydrocodone
CYP2D6, ABCB1, COMT
Methadone
CYP2D6, UGT2B7, ABCB1, OPRM1
Ibuprofen
CYP2C9
Diclofenac
Naproxen

35. Pharmacogenomic Associations: Adjuvants
Drug Class
Actionable Genes
Dosing Guideline
Tricyclic Antidepressants (TCAs)
(e.g., amitriptyline, doxepin, desipramine, imipramine, nortriptyline)
CYP2D6, CYP2C19
CPIC
Selective Serotonin Reuptake Inhibitors (SSRIs)
(e.g., citalopram, escitalopram)
CYP2C19
Anticonvulsants
(e.g., carbamazepine)
HLA-B

36. Codeine Pharmacogenomic Pathway
Source:

37. CYP2D6 Codeine Metabolism Phenotypes
Crews et al. Clin Pharmacol & Ther ;95(4):

38. Codeine CPIC Guideline
Crews et al. Clin Pharmacol & Ther ;95(4):

40. Tramadol Pharmacogenomic Pathway
Source:

41. Tramadol Dosing Guideline
Swen et al. Clin Pharmacol & Ther. 2011;89(5):

42. Oxycodone Dosing Guideline
Swen et al. Clin Pharmacol & Ther. 2011;89(5):

43. Cytochrome P450 Drug Interactions

44. Verbeurgt et al. Pharmacogenomics. 2014;5(5):655-65.
Drug Interactions
Drug-drug interactions (DDI):
Occurs when 2 or more drugs interact in such a way that the effectiveness and/or toxicity of one of those agents is affected.
Drug-gene interactions (DGI):
Occurs when genotype (e.g., CYP2D6 poor metabolizer) affects the patient’s ability to clear a drug.
Drug-drug-gene interactions (DDGI):
Occurs when genotype and another drug in patient’s regimen (e.g., CYP2D6 inhibitor) affect a patient’s ability to clear a drug.
Verbeurgt et al. Pharmacogenomics. 2014;5(5):

45. Drug Interactions Classification of Medications in CYP450 DDGI:
Substrates:
drugs that are metabolized as substrates by the enzyme
Inhibitors:
drugs that prevent the enzyme from metabolizing the substrates
Activators (inducer):
drugs that increase the enzyme's ability to metabolize the substrates

46. P450 Drug-Drug-Gene Interactions
Substrates
2D6 Inhibitors
Inducers
codeine
tramadol
Oxycodone
TCAs
bupropion
cinacalcet
fluoxetine
paroxetine
quinidine
diphenhydramine
duloxetine
sertraline
terbinafine
amiodarone
Cimetidine
dexamethasone
rifampin
Strong inhibitor: a > 5-fold increase in the plasma AUC values or more than 80% decrease in clearance.
Moderate inhibitor: a > 2-fold increase in the plasma AUC values or 50-80% decrease in clearance.
Weak inhibitor: a > 1.25-fold but < 2-fold increase in the plasma AUC values or 20-50% decrease in clearance.
Complete Flockhart Table™ at

47. Implications for Pain Management Practice

48. Clinical Implications
Patient assessment –
Understand relationship between genetics & health.
Link medication history, medication regimen, and drug responses.
Identify at risk individuals who may have altered drug effects.
Assist in identifying the most optimal analgesic medication.
Patient education –
Interpreting genetic test results. (Case study)
Provide patients with information & resources for informed decision making.
Self-monitoring for drug effectiveness & adverse effects.
Referrals –
Facilitate referrals for specialized genetic & genomic services.

49. Clinical Implications
Implementing PGx Testing Into Practice:
Pharma
Pharmacogenomic Alert
Evaluate & implement best practices
Integration with electronic health record
Strong Risk of Therapeutic Failure*
CYP2D6 *4/*4 (Poor Metabolizer)
Patient prescribed codeine
Implications:
Greatly reduced morphine formation following codeine administration, leading to insufficient pain relief
Management Recommendation:
Avoid codeine use due to lack of efficacy. Consider alternative analgesics such as morphine or a non-opiod. Consider avoiding tramadol.
*CPIC Dosing Guideline for codeine and CYP2D6:
* Clinical Pharmacogenetics Implementation Consortium (CPIC) CPIC guidelines reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision making P
Request Pharmacogenetic Consult
No thanks, continue with order
Change Rx
Levy et al. CPT. 2014; 93(3):

50. Clinical Implications
Cost of testing
Ranges from $
Insurance coverage
Most insurance plans consider vast majority of PGx testing “experimental”
Medicare's "Coverage with Evidence Development" policy may cover a pharmacogenetic test if a patient has "appropriate" indications
Ethical considerations

51. Online Pharmacogenomic Resources For Clinicians
The Pharmacogenomics Knowledgebase (PharmGKB):
Clinical Pharmacogenomics Implementation Consortium (CPIC):
Flockhart Table of CYP450 Drug Interactions:
FDA Table of PGx Biomarkers in Drug Labeling:
Implementing Genomics in Practice (IGNITE):
My Drug Genome:
Genetics/Genomics Competency Center (G2C2):
PharmGKB presents pharmacogenomic information relevant to clinical care on subjects such as dosing guidelines, drug labels, gene-drug interactions, and genotype-phenotype relationships.
CPIC provides guidelines centering on gene/drug interactions to assist providers in implementing pharmacogenetic tests into clinical practice. These guidelines are freely available, peer-reviewed, updatable, and intended to help in translating lab test results into actionable prescribing decisions.  
My Drug Genome is a knowledge resource for patients and providers about using genetics to choose the best medications for patients.
G2C2: This website provides high quality educational resources for group instruction or self-directed learning in genetics/genomics by health care educators and practitioners.

52. Mitchell Knisely, PhD, RN-BC, ACNS-BC
Contact Information:
Mitchell Knisely, PhD, RN-BC, ACNS-BC