CENTER FOR INDIVIDUALIZED MEDICINE Pharmacogenomics for Your Practice

CENTER FOR INDIVIDUALIZED MEDICINE Pharmacogenomics for Your Practice Eric T. Matey, Pharm. D. , RPh. BC W. T. Nicholson, MD, Pharm. D, MSc, DABCP, Pharmacogenomics Consultant, Gastroenterology & Hepatology BCPS Center for Individualized Medicine Everett J. and Jane M. Hauck Associate Consultant, Department of Anesthesiology Konstantinos N. Lazaridis, MD Director, Center for Individualized Medicine, Professor of Medicine Medication Therapy Management Chair Pharmacogenomics Task Force Assistant Professor of Anesthesiology and Pharmacology © 2012 MFMER | slide-1

Disclosure Dr. Nicholson No Relevant Disclosures Scientific Investigator for Mayo Currently working with industry partners on study design and drug-drug interaction studies. I receive no direct personal compensation from consultation or clinical trials. Dr. Matey No Disclosures Dr. Lazaridis No Disclosures Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-2

Objectives At the conclusion of this session, participants should be able to: Describe fundamental concepts of pharmacogenomics outlined in this presentation Discuss clinical outcomes resulting from the implementation of pharmacogenomics panel testing Identify the impact of pharmacogenomics in the prescriber practice Describe the clinical efforts underway in clinical practice Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-3

Adverse Drug Reactions in the U. S. : (1994) 2. 2 million hospitalizations 106, 000 patient deaths per year 4 th leading cause of death in US $136 billion in health care costs annually Lazarou et al, JAMA, 279: 1200 -5, 1998 Johnson et al, Arch Intern Med, 155: 1949 -56, 1995 Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-4

Leading Causes of Death in US 2013 Heart disease: 611, 105 Cancer: 584, 881 Chronic lower respiratory diseases: 149, 205 Accidents (unintentional injuries): 130, 557 Stroke (cerebrovascular diseases): 128, 978 Adverse Drug Reactions 106, 000 (1994) –Not included in CDC list? Alzheimer's disease: 84, 767 Diabetes: 75, 578 Influenza and Pneumonia: 56, 979 Nephritis, nephrotic syndrome, and nephrosis: 47, 112 Source: Deaths: final data. CDC Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-5

Factors Related to Drug Responses Intrinsic factors: Age, gender Race/ethnicity Disease states, organ dysfunctions Genetics Physiological changes: Pregnancy, lactation Extrinsic factors: Smoking/Et. OH Diet Concomitant medications Compliance of taking medications Center for INDIVIDUALIZED MEDICINE Huang SM, Goodsaid F, Rahman A, et el. Toxicology Mechanisms and Methods. 2006; (16) 89 -99. © 2012 MFMER | slide-6

Current Drug-Gene Pairs at Mayo Carbamazepine –HLA-B*1502 & HLA-A*3101 Abacavir - HLA-B*5702 Allopurinol - HLA-B*5801 Codeine - CYP 2 D 6 Tramadol - CYP 2 D 6 Tamoxifen - CYP 2 D 6 Fluoxetine, Paroxetine, Fluvoxamine - CYP 2 D 6 Venlafaxine - CYP 2 D 6 Clopidogrel - CYP 2 C 19 Citalopram, Escitalopram - CYP 2 C 19 Warfarin - CYP 2 C 9/VKORC 1 Thiopurines -TPMT Simvastatin - SLCO 1 B 1 Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-7

PGx education for Pharmacists 1. PGx 101 2. Hypersensitivity Abacavir Carbamazepine 3. Cardiovascular Simvastatin Clopidogrel 4. CYP 2 D 6 5. TPMT Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-8

PGx Profile Service Patient interest: CIM Champion orders PGx Express Service IM Clinic Pharmacist Consult Mayo Lab Sequencing, Analysis and Results: EMR Result and One. Ome Report in patient record © 2012 MFMER | slide-9 Patient Sample Acquisition Results Returned to Center for INDIVIDUALIZED MEDICINE Patient by Pharmacist

How many genes are currently tested in the PGx panel offered by the IM Clinic? A. B. C. D. 5 genes 9 genes 22 genes 15 genes Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-10

Case 1: Sam Initial Presentation: 76 year old male DM, Hypercholestrolemia, Pain, MDD, BPH, RLS Hx of multiple opioid use with persistent pain Medications: Current: Lantus , Hemalog, Aspirin, Oxycodone, Paroxetine, Pramiprexole, Simvastatin, Lisinopril, Tamsulosin, Vit B&E supplements Side Effects: Respiratory Sx, chronic constipation and dizziness Action: After medication reconciliation performed, 9 -gene pharmacogenomics panel ordered Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-11

Given the HPI of this patient which gene would you test for? A. B. C. D. CYP 2 C 19 HLA B*5801 CYP 2 D 6 SLCO 1 B 1 Medications: Current: Lantus , Hemalog, Aspirin, Oxycodone, Paroxetine, Pramiprexole, Simvastatin, Lisinopril, Tamsulosin, Vit B&E supplements Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-12

Case 1: Genetic Test Results Gene(Metabolizing Genotype Enzyme) Phenotype CYP 2 C 9 *2/*3 Poor to Intermediate CYP 2 D 6 *35/*41 Intermediate to Extensive VKORC 1 *2/*3 -1639 GG Intermediate sensitivity CYP 3 A 4 *1/*1 Extensive CYP 3 A 5 *3/*3 Poor (Normal) SLCO 1 B 1 *1/*1 Normal Risk HLA-B*5801 Negative Normal Risk CYP 1 A 2 Multiple Variations Extensive to Ultrarapid CYP 2 C 19 *1/*1 Extensive Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-13

Case 1: Drug-Gene Interactions Sam’s Medication Hx Metabolizing Enzyme Phenotype Oxycodone CYP 2 D 6 Intermediate to Extensive Paroxetine CYP 2 D 6 Intermediate to Extensive Simvastatin SLCO 1 B 1 Normal risk Tamsulosin CYP 3 A 4 Extensive Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-14

Case 1: Recommendations for Sam Recommend tapering off oxycodone Recommend avoiding tramadol/codeine Paroxetine, a major inhibitor of CYP 2 D 6 Paroxetine is also a substrate of CYP 2 D 6 Consider discontinuing paroxetine and use alternative Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-15

Case 2: Ted Initial Presentation: 16 year old male POTS and autism spectrum and on multiple medications Medications: ► Current: lubiprostone , methylphenidate, florastor , guanfacine, risperidone, propranolol, atomoxetine, sertraline, midodrine ► PMH: metoprolol, miralax, dulcolax ► ► Side Effects: ► Patient reports extreme fatigue from metoprolol Action: ► Medication reconciliation performed and CYP 2 D 6, CYP 2 C 19, CYP 3 A 4 and CYP 1 A 2 gene testing ordered Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-16

Case 2: Genetic Test Results Gene Genotype (Metabolizing enzyme) Phenotype CYP 2 C 19 *2/*2 Poor CYP 2 D 6 *1/*3 Intermediate CYP 3 A 4 *1/*22 Intermediate to Extensive CYP 1 A 2 Multiple Variations Extensive Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-17

Case 2: Drug-Gene Interactions Ted’s Medication Hx Metabolizing Enzyme Phenotype midodrine CYP 2 D 6 (prodrug) Intermediate propranolol CYP 2 D 6 Intermediate risperidone CYP 2 D 6, CYP 3 A 4 Intermediate, Intermediate to Extensive atomoxetine CYP 2 D 6 Intermediate Metoprolol CYP 2 D 6 Intermediate sertraline CYP 2 C 19, many others Poor Lubiprostone None n/a methylphenidate CES 1 n/a Florastor None N/a Guanfacine ER CYP 3 A 4 Intermediate to Extensive Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-18

Which of the following medications is an inhibitor of CYP 2 D 6 A. B. C. D. Methylphenidate Propranolol Sertraline Midodrine Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-19

Substrates , Inhibitors, Inducers Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-20

Case 2: Ted Case Complications ► Multiple Polymorphism ► CYP 2 C 19, CYP 2 D 6 and CYP 3 A 4 ► Drug/Drug Interactions ► Risperidone/midodrine (CYP 2 D 6) ► Drug Enzyme/Gene Interactions ► Inhibitors (Methylphenidate) ► Inducers Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-21

Case 2: Recommendations for Ted Methylphenidate: weak inhibitor of CYP 2 D 6 Potential for phenoconversion from IM to PM Recommend close monitoring of guanfacine, propranolol, sertraline and risperidone Risperidone was tapered off Avoid Metoprolol: CYP 2 D 6 - IM Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-22

Where Can I find More Information? Mayo Clinic: Ask. Mayo. Expert http: //mayoweb. mayo. edu/ Expert Directory Physicians Pharmacists Mayo Clinic Center for Individualized Medicine (Internal) http: //intranet. mayo. edu/charlie/center-individualized-medicine/ Mayo Clinic Center for Individualized Medicine (External) http: //mayoresearch. mayo. edu/center-for-individualized-medicine/ Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-23

Precision Medicine Initiative Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-24

Why Offering PGx Testing $136, 000, 00 US FDA 2015 Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-25

Mayo Clinic RIGHT Protocol 1, 000 Clinical Genomics for Every Patient Everywhere 3% 1% * N=1013 10% * 18% 31% 37% PGx variant in 0 gene PGx variant in 1 gene PGx variants in 2 genes PGx variants in 3 genes PGx variants in 4 genes PGx variant in 5 genes Center for INDIVIDUALIZED MEDICINE Yuan, Black, et al. – J. Mol. Diagnostics, “in press” © 2012 MFMER | slide-26

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Elements of Clinical PGx Practice Medical champion Eric Matey, Pharm. D DLMP test (CLIA/CAP) Integrated report: from One. Ome (joint Mayo venture) EMR: Clinical Decision Alerts Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-28

Current Mayo PGx Gene Panel Genes Medications CYP 1 A 2 CYP 2 C 9 CYP 2 C 19 CYP 2 D 6 CYP 3 A 4 CYP 3 A 5 VKORC 1 SLC 01 B 1 HLA-B*58: 01 Multiple drugs impacted Warfarin resistance Simvastatin myopathy Allopurinol sensitivity Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-29

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Existing Clinic PGx Offerings Executive Medicine International Clinic Pre-Emptive Mayo Referral. Patient request New Patient Self Referral: Preventive Services Clinic Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-31

Mayo’s Planned PGx Expansion Making Prescriptions Personal Affordable testing Interactive and integrated report Provider education and EMR rules Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-32

Upcoming One. Ome PGx Gene Panel Test Covering 300+ Drugs GENE ALLELES CYP 1 A 2 1 D, 1 F, 1 J, 1 K, 1 L, 1 W F 5 1691 G>A CYP 2 B 6 *3, *4, *5, *6, *18 OPRM 1 118 A>G CYP 2 C 19 *2, *3, *4 B, *10, *17, *18 COMT 322 G>A (Val 158 Met) CYP 2 C 9 *2, *3, *4, *5, *6, *8, *11, *18 DRD 2 939 A>G, -241 A>G, CYP 2 D 6 *2 A, *2, *3, *4 N, *4 M, *5, *6, *7, *9, *10, *11, *12, *13, *14, *15, *17, *18, *20, *21, *29, *31, *35, *36, *41, *42, *58, *63, *64, *68, *69, *70, *91, *109 HTR 2 C -759 C>T CYP 3 A 4 *1 B, *22 HTR 2 A IN 2 T>C, 1354 C>T, 102 T>C, 1438 G>A CYP 3 A 5 *3, *6, *7 DPYD *2 A, *13, 97547947 T>A SLCO 1 B 1 *5, *17 TPMT *2, *3 A, *3 B, *3 C, *4 UGT 1 A 1 TA 6, TA 7 GRIK 4 120663363 T>C VKORC 1 -1639 G>A MTHFR 677 C>T, 1298 A>C F 2 2021 G>A SLC 6 A 4 La/Lg/S IL 28 B 39248147 C>T Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-33

Timing is Everything! Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-34

Number of PGX Tests Scaling of PGx Use and Barriers Engagement and education of practitioners Cost of PGx Need for Pharmacist Resources and Expertise Time Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-35

Center for Individualized Medicine Clinomics 2016 Grow PGx use for patients: with the successful launch of One. Ome’s test at a highly reduced price point, IM Clinic goals are to: • Implement multiple “Practice Improvement Projects” with priority partners • Expand current active clinical services in Rochester • Activate clinical service standardly in FL and AZ • Build processes and elements with stretch goals to: PGx and Aging Offer PGx Profile to every exec med patient next year PGx Motility Study Offer PGx Profile Service to MCHS and then MCCN PGx with Neurosurgery (Spine) PGx with Transplant (Heart, Lung and Pancreas) PGx with Peds Pain PGx with Fibromyalgia PGx with Peds GIH Center for INDIVIDUALIZED MEDICINE PGx with OBGYN © 2012 MFMER | slide-36 36

PGx Practice Improvement Projects GIH Motility Clinic Why: 726 patients -7702 discrete medications 60% were taking one psychotropic agent 29% were taking two or more Champion: Adil Bharucha, MD Scope: Examine if PGx testing improves the symptoms of patients with motility problems Test: Center for INDIVIDUALIZED MEDICINE One. Ome 23 gene PGx panel © 2012 MFMER | slide-37

Results from preemptive PGx testing for 10000 participants will be available in the EMR A. True B. False Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-38

Mayo Clinic RIGHT Protocol 10, 000 Mayo – Baylor collaboration 76 pharmacogenes for 10, 000 Mayo Biobank participants Sequenced pre-emptively and placed in EMR Systematic evaluation of outcomes Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-39

Take Home Message PGx is here to stay and will be a key part of practice PGx testing is becoming affordable Comprehensive drug – gene coverage and clinical decision support rules are available We need to educate practitioners on the use of PGx and Pharmacist resources to improve patient care Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-40

Questions Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-41

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