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Precision Healthcare:
Pharmacogenomics & Pain Management
Mitchell Knisely, PhD, RN-BC, ACNS-BC
Postdoctoral Scholar
University of Pittsburgh School of Nursing
February 7, 2017
Overview of Presentation
• Advances
in Genomic Science
• Foundations
Practice
of Pharmacogenomics & Translation to
• Pharmacogenomics
& Pain Management
• Cytochrome
P450 Drug Interactions
• Implications
for Practice
“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)
Advances in
Genomic Science
Human Genome Project
1990-2003
• 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 2000
and published in February 2001
“…the most important, most wondrous map ever produced by humankind.”
– President Clinton
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
Post-Human Genome Project Era
2003 - present
Collins et al. Nature. 2003;422(6934):835-47.
The International Genome Sample Resource:
http://www.internationalgenome.org/about
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.
Precision Medicine Initiative ®
•
Announced by President Obama at 2015
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.
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.
Foundations of
Pharmacogenomics &
Translation to Clinical
Practice
“Current” Medical Paradigm
“One-size-fits all approach”
What is Pharmacogenomics?
•
Study of genomic variations associated
with drug response.
•
Understand how genetic variation
contributes to variability in drug
disposition, response, & toxicity.
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.”
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.
Factors Affecting Pharmacokinetics &
Pharmacodynamics of Drugs
Pharmacokinetics
Prescribed
dosing regimen
Pharmacodynamics
Drug
effects
Drug at site of
action
• 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.
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.
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.
Genetic Variants’ Clinical Impact on Drug
Metabolism
Gain-of-function
Mutation
Wild Type Allele
Loss-of-Function
Mutation
↑ drug-metabolizing
enzyme activity
Normal drugmetabolizing enzyme
activity
No or ↓ drugmetabolizing enzyme
activity
Active Drug
Little or No Active
Drug
Appropriate
Dose
↑ Active Drug
Exposure
Pro Drug
↑ Active Drug
Exposure
Appropriate
Dose
Little or No Active
Drug
Brazeau, D. (2015). Basics of pharmacogenomics. In D. Lea, D. Cheek, D. Brazeau, & G. Brazeau (eds.), Mastering Pharmacogenomics. Indianapolis, IN: STTI.
Drug Metabolizing Phenotypes
Phenotype
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
Translating Pharmacogenetic Testing
to Clinical Practice
Mitigate/Cure
Pharmacogenetic
Test
Administer
drug
Genotype
Phenotype
Adverse drug effect
Select
alternative
drug/adjust
dosing
Pharmacogenomic Practice Resources
U.S. Food & Drug Administration (FDA):
 > 170 drugs have pharmacogenomic information on drug labels.
Source: http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
Pharmacogenomic Practice Resources
•
PharmGKB: www.PharmGKB.org
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.
Elements of CPIC Guidelines
•
Introduction
•
Focused Literature Review
•
Gene:





•
Background
Genetic Test Interpretation
Available Genetic Test Options
Incidental findings
Other considerations
Drug(s):
 Background
 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
 Other considerations
•
Potential Benefits and Risks for the Patient
•
Caveats: Appropriate Use and/or Potential Misuse of Genetic Tests
Source: www.pharmgkb.org/page/cpic
Pharmacogenomic Practice Resources
NCBI – Genetic Testing Registry (GTR):
Access to other resources on NCBI: www.ncbi.nlm.nih.gov/guide/genes-expression/.
Pharmacogenomics &
Pain Management
Benefits of Pharmacogenomics in
Pain Management
• Improved
• Ability
drug safety.
to optimize individual therapies.
Drug Safety - Codeine
http://www.fda.gov/Drugs/DrugSafety/ucm339112.htm
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.
Genetic Factors Influencing Analgesic
Response
• Pharmacokinetic
Factors
 Drug-metabolizing enzymes
 CYP2D6, CYP3A4
 Drug elimination
 UGT2B7
 Drug transporters
 ABCB1, MDR1
• Pharmacodynamic
 Drug receptors
 OPRM1, OPRK1
 Signal transduction
 COMT, STAT6
Factors
Opioid Signaling Pathway
Laugsand et al. European Journal of Cancer. 2011;47:1682-1691.
Well-Known Pharmacogenomic
Associations: Analgesics
Analgesic
Genes
Dosing Guideline
Acetaminophen
CYP1A2, CYP2D6, CYP2E1, CYP3A4
None
Celecoxib
CYP2C9, CYP2D6
None
Codeine*
CYP2D6, CYP3A4, UGT2B4, UGT2B7
Fentanyl
CYP3A4
None
Oxycodone
CYP2D6
DPWG
Tramadol*
CYP1A2, CYP2D6, CYP2E1, CYP3A4
DPWG
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
CPIC, DPWG, PRO
Pharmacogenomic Associations:
Analgesics
Analgesic
Genes
Morphine
UGT2B7, ABCB1, COMT, OPRM1, CGH1
Hydrocodone
CYP2D6, ABCB1, COMT
Methadone
CYP2D6, UGT2B7, ABCB1, OPRM1
Ibuprofen
CYP2C9
Diclofenac
CYP2C9
Naproxen
CYP2C9
Pharmacogenomic Associations:
Adjuvants
Drug Class
Actionable Genes
Dosing Guideline
CYP2D6, CYP2C19
CPIC
CYP2C19
CPIC
HLA-B
CPIC
Tricyclic Antidepressants (TCAs)
(e.g., amitriptyline, doxepin, desipramine,
imipramine, nortriptyline)
Selective Serotonin Reuptake
Inhibitors (SSRIs)
(e.g., citalopram, escitalopram)
Anticonvulsants
(e.g., carbamazepine)
Codeine Pharmacogenomic Pathway
Source: www.pharmgkb.org
CYP2D6 Codeine Metabolism Phenotypes
Crews et al. Clin Pharmacol & Ther. 2014;95(4):376-382.
Codeine CPIC Guideline
Crews et al. Clin Pharmacol & Ther. 2014;95(4):376-382.
Tramadol Pharmacogenomic Pathway
Source: www.pharmgkb.org
Tramadol Dosing Guideline
Swen et al. Clin Pharmacol & Ther. 2011;89(5):662-673.
Oxycodone Dosing Guideline
Swen et al. Clin Pharmacol & Ther. 2011;89(5):662-673.
Cytochrome P450 Drug
Interactions
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):655-65.
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
P450 Drug-Drug-Gene Interactions
Substrates
2D6 Inhibitors
Inducers
codeine
tramadol
Oxycodone
bupropion
cinacalcet
fluoxetine
paroxetine
quinidine
diphenhydramine
dexamethasone
rifampin
TCAs
duloxetine
sertraline
terbinafine
amiodarone
Cimetidine
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 http://medicine.iupui.edu/clinpharm/ddis/main-table.
Implications for Pain
Management Practice
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.
Clinical Implications
Implementing PGx Testing Into Practice:
Pharmacogenomic Alert
• Evaluate
& implement best
practices
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
Pharma
Management Recommendation:
• Integration
with electronic
health record
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:
www.pharmgkb.org
* 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
Levy et al. CPT. 2014; 93(3): 307-309
Change Rx
Clinical Implications
• Cost
of testing
 Ranges from $250-500
• 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
Online Pharmacogenomic Resources
For Clinicians
•
The Pharmacogenomics Knowledgebase (PharmGKB): https://www.pharmgkb.org/
•
Clinical Pharmacogenomics Implementation Consortium (CPIC): https://cpicpgx.org/
•
Flockhart Table of CYP450 Drug Interactions: http://medicine.iupui.edu/CLINPHARM/DDIS
•
FDA Table of PGx Biomarkers in Drug Labeling:
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
•
Implementing Genomics in Practice (IGNITE): https://ignite-genomics.org/
•
My Drug Genome: http://www.mydruggenome.org/overview.php
•
Genetics/Genomics Competency Center (G2C2): http://genomicseducation.net/
Contact Information:
Mitchell Knisely, PhD, RN-BC, ACNS-BC
[email protected]