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 of Pharmacogenomics & Translation to Practice Pharmacogenomics & Pain Management Cytochrome P450 Drug Interactions Implications for Practice

(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)

Advances in Genomic Science

“…the most important, most wondrous map ever produced by humankind.” 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 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.

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 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.

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

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

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): 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: 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 drug safety. Ability 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 Pharmacodynamic Factors Drug-metabolizing enzymes Drug receptors CYP2D6, CYP3A4 OPRM1, OPRK1 Drug elimination Signal transduction UGT2B7 COMT, STAT6 Drug transporters ABCB1, MDR1

Opioid Signaling Pathway Laugsand et al. European Journal of Cancer. 2011;47:1682-1691.

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

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

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

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

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):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 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 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: 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: 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 Change Rx Levy et al. CPT. 2014; 93(3): 307-309

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/ 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.

Mitchell Knisely, PhD, RN-BC, ACNS-BC Contact Information: Mitchell Knisely, PhD, RN-BC, ACNS-BC mik126@pitt.edu