CENTER FOR INDIVIDUALIZED MEDICINE Pharmacogenomics in the Modern

Conflict of Interest Disclosure I have no financial or relevant conflict of interest to

Have you. . Received direct-to-consumer genetic testing? Had pharmacogenomics (PGx) testing? Had a patient

Objectives Describe the rationale, basic concepts, and the role of pharmacogenomics (PGx) in variation

Past President Obama on Personalized Medicine “Tonight, I’m launching a new Precision Medicine Initiative

Leading causes of Death in US (2015) Heart disease: 635, 260 Cancer: 598, 038

Drug-related morbidity & mortality $528 billion annually Was $136 billion in 1994 16% of

Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-8

Factors Related to Drug Responses Intrinsic factors: • • Age, gender Race/ethnicity Disease states,

What is pharmacogenomics? Study of genetic variations that influence individual response to drugs Same

Three domains of pharmacogenomics effects 1 Hypersensitivity 2 3 Efficacy Toxicity Center for INDIVIDUALIZED

Metabolizer status & drug exposure Poor metabolizer Intermediate Normal Rapid Ultrarapid Legend Active Drug

Metabolizer Status may impact drugs differently Active Drug Prodrug Active Inactive Poor metabolizer =

Alteration of Metabolizer Status In addition to genetic variation, other drugs/foods can impact drug

Nomenclature Nelson, DR, Pharmacogenetics 1996; 6. 1– 42 Center for INDIVIDUALIZED MEDICINE © 2012

What we know vs. what we don’t 509 drug labels with genetic information 100

Common PGx Panel test report format styles © 2012 MFMER | slide-17

Stoplight format Red: Major gene-drug interaction Yellow: Moderate genedrug interaction Green: Minimal or no

Drug-specific format Drug-specific comments or recommendations Example PGx Report Drug A: Reduce starting dose

PGx hypersensitivity example © 2012 MFMER | slide-20

pt or HLA-B*58: 01 & Allopurinol 1 T- ce ll r ec e :

Allopurinol & HLA-B*58: 01 Severe cutaneous adverse reaction (SCAR) 0. 1% - 0. 4%

When to test for HLA-B*58: 01 What we know… Most common in patients of

Allopurinol take home points Asian descent + starting allopurinol Screen for HLA-B*58: 01 positive

PGx Case examples © 2012 MFMER | slide-25

Case 1: Judy Initial Presentation: 72 year old female, Japanese ethnicity PMH: Major Depressive

Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-27

Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-28

Case 1: Drug-Gene Interactions Medication Sertraline Allopurinol Citalopram Escitalopram Gene CYP 2 C 19

Pharmacogenomics resources www. pharmgkb. org--> 100 medications Clinical Pharmacogenomics Implementation Consortium (CPIC) Dutch Pharmacogenetic

CPIC guidelines: SSRIs Phenotype Citalopram & escitalopram recommendation Sertraline recommendation Ultrarapid Consider an alternative

Pantoprazole pharmacology Pantoprazole CYP 2 C 19 Inactive Metabolite Center for INDIVIDUALIZED MEDICINE M.

Dutch Pharmacogenomic Working Group (DWPG) guidelines CYP 2 C 19 phenotype Recommendations Ultrarapid metabolizer

Case 1: Plan for Judy Switch allopurinol to febuxostat Switch sertraline to fluoxetine PGx

“Could Pharmacogenomics help my patient? ” Karen’s Story Youtube link Center for INDIVIDUALIZED MEDICINE

Summary Pharmacogenomics is one of many variables in drug response Consider active drug vs.

Acknowledgements Center for Individualized Medicine (CIM) CIM Education Pharmacogenomic Task Force Ask Mayo Expert

QUESTIONS? Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-38

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CENTER FOR INDIVIDUALIZED MEDICINE Pharmacogenomics in the Modern Healthcare Setting Jessica Wright, Pharm. D, BCACP Pharmacogenomics Medication Therapy Management Pharmacist Center for Individualized Medicine Mayo Clinic © 2012 MFMER | slide-1

Have you. . Received direct-to-consumer genetic testing? Had pharmacogenomics (PGx) testing? Had a patient with PGx test results? Had a patient who asked you PGx-related questions? Heard of the approximate cost 2 years ago? Now? Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-3

Objectives Describe the rationale, basic concepts, and the role of pharmacogenomics (PGx) in variation of response to medications Describe where to find available PGx guidelines and other resources Develop an individualized medication plan for a patient presenting with pharmacogenomic test results Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-4

Past President Obama on Personalized Medicine “Tonight, I’m launching a new Precision Medicine Initiative to bring us closer to curing diseases like cancer and diabetes - and to give all of us access to the personalized information we need to keep ourselves and our families healthier. ” Past President Obama State of the Union Address Jan 20, 2015 Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-5

Leading causes of Death in US (2015) Heart disease: 635, 260 Cancer: 598, 038 Accidents (unintentional injuries): 161, 374 Chronic lower respiratory diseases: 154, 596 Stroke (cerebrovascular diseases): 142, 142 Alzheimer's disease: 116, 103 Diabetes: 80, 058 Drug-induced causes: 55, 403 Influenza & pneumonia: 51, 537 Nephritis, nephrotic syndrome, and nephrosis: 50, 046 Intentional self-harm (suicide): 44, 965 Center for INDIVIDUALIZED MEDICINE Murphy SL, et al. Deaths: Final Data for 2015. National Vital Statistics Reports. 2017; 66(6): 1 -73. © 2012 MFMER | slide-6

Drug-related morbidity & mortality $528 billion annually Was $136 billion in 1994 16% of total US health care expenditures (2016) Watanabe JH, et al. Ann Pharmacother. 2018 Sep; 52(9): 829 -37 © 2012 MFMER | slide-7 Center for INDIVIDUALIZED MEDICINE

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 Medication compliance Center for INDIVIDUALIZED MEDICINE Huang SM, Goodsaid F, Rahman A, et el. Toxicology Mechanisms and Methods. 2006; (16) 89 -99. © 2012 MFMER | slide-9

What is pharmacogenomics? Study of genetic variations that influence individual response to drugs Same Condition No Response Desired Response Toxic Side Effects Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-10

Metabolizer Status may impact drugs differently Active Drug Prodrug Active Inactive Poor metabolizer = too much drug Metoprolol is metabolized by CYP 2 D 6 then eliminated Inactive Active Poor metabolizer = too little drug Tamoxifen is converted to its active metabolite by CYP 2 D 6 Center for INDIVIDUALIZED MEDICINE M. Whirl-Carrillo, E. M. Mc. Donagh, J. M. Hebert, L. Gong, K. Sangkuhl, C. F. Thorn, R. B. Altman and T. E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414 -417. © 2012 MFMER | slide-13

Alteration of Metabolizer Status In addition to genetic variation, other drugs/foods can impact drug metabolism Inducer: increases enzyme activity Inhibitor: decreases enzyme activity Center for INDIVIDUALIZED MEDICINE Horn JR. (2018) Basic and Clinical Pharmacology. Retrieved from https: //accessmedicine. mhmedical. com/content. aspx? bookid=2249&sectionid=175226529#11 © 2012 MFMER | slide-14 48443525

What we know vs. what we don’t 509 drug labels with genetic information 100 drugs with dosing guidelines Pharm. GKB. www. pharmgkb. org Accessed 21 Sep 2018. Center for INDIVIDUALIZED MEDICINE M. Whirl-Carrillo, E. M. Mc. Donagh, J. M. Hebert, L. Gong, K. Sangkuhl, C. F. Thorn, R. B. Altman and T. E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine"Clinical Pharmacology & © 2012 MFMER | slide-16 Therapeutics (2012) 92(4): 414 -417.

Stoplight format Red: Major gene-drug interaction Yellow: Moderate genedrug interaction Green: Minimal or no gene-drug interaction - OR - Major -Drug A Moderate -Drug B & C Minimal / None - Drug D, E & F Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-18

Drug-specific format Drug-specific comments or recommendations Example PGx Report Drug A: Reduce starting dose by 50% and titrate cautiously Drug B: Standard dosing recommended Drug C: Consider alternative therapy due to increased risk of therapeutic failure Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-19

pt or HLA-B*58: 01 & Allopurinol 1 T- ce ll r ec e : 0 8 *5 B A L H T-cell Keratinocyte Allopurinol - peptide complex Immune mediators Hershfield MS, et al. Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing. Clin Pharmacol Ther. 2013 Feb; 93(2): 153 -8. © 2012 MFMER | slide-21 Center for INDIVIDUALIZED MEDICINE

Allopurinol & HLA-B*58: 01 Severe cutaneous adverse reaction (SCAR) 0. 1% - 0. 4% risk of SCAR Up to 25 -30% mortality with most severe form of SCAR Photo courtesy of: http: //blogs. bmj. com/bmj/files/2012/02/toxic_epidermal_necrolysis. jpg Center for INDIVIDUALIZED MEDICINE Hershfield MS, et al. Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing. Clin Pharmacol Ther. 2013 Feb; 93(2): 153 -8. © 2012 MFMER | slide-22

When to test for HLA-B*58: 01 What we know… Most common in patients of Asian descent Least common in patients of European descent CPIC guidelines No guidance on when to test 2012 American College of Rheumatology Guidelines [Gout] Recommends testing: Korean descent with stage 3 or worse CKD Thai Han Chinese Center for INDIVIDUALIZED MEDICINE Saito, et al. Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update. Supplemental material. Clin Pharmacol Ther. 2016 Jan; 99(1): 36 -7. © 2012 MFMER | slide-23

Allopurinol take home points Asian descent + starting allopurinol Screen for HLA-B*58: 01 positive Avoid allopurinol Negative HLA-B*58: 01 doesn’t exclude possibility of SCAR Especially in Caucasians Center for INDIVIDUALIZED MEDICINE Saito, et al. Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for Human Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing: 2015 update. Supplemental material. Clin Pharmacol Ther. 2016 Jan; 99(1): 36 -7. © 2012 MFMER | slide-24

Case 1: Judy Initial Presentation: 72 year old female, Japanese ethnicity PMH: Major Depressive Disorder Gout Barrett’s esophagus Citalopram and escitalopram were not effective at max doses. On sertraline 200 mg daily x 4 months with only minimal improvement. Due to multiple inefficacies, pharmacogenomics testing ordered Medications: Aspirin, allopurinol (started 3 days ago), sertraline, pantoprazole Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-26

Case 1: Drug-Gene Interactions Medication Sertraline Allopurinol Citalopram Escitalopram Gene CYP 2 C 19 HLAB*58: 01 CYP 2 C 19 Phenotype Ultrarapid metabolizer Positive Ultrarapid metabolizer Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-29

Pharmacogenomics resources www. pharmgkb. org--> 100 medications Clinical Pharmacogenomics Implementation Consortium (CPIC) Dutch Pharmacogenetic Working Group Canadian Pharmacogenomics Network for Drug Safety Pharmacists PGx is similar to a drug-drug interaction Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-30

CPIC guidelines: SSRIs Phenotype Citalopram & escitalopram recommendation Sertraline recommendation Ultrarapid Consider an alternative drug not metabolized by CYP 2 C 19 Initiate with recommended starting dose. If patient doesn’t respond to recommended maintenance dosing, consider an alternative drug not predominantly metabolized by CYP 2 C 19 Normal or Intermediate Standard dosing recommended Poor metabolizer Consider a 50% reduction of starting dose and titrate to response or select an alternative drug. Center for INDIVIDUALIZED MEDICINE M. Whirl-Carrillo, E. M. Mc. Donagh, J. M. Hebert, L. Gong, K. Sangkuhl, C. F. Thorn, R. B. Altman and T. E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine"Clinical Pharmacology & Therapeutics (2012) 92(4): 414 -417. © 2012 MFMER | slide-31

Pantoprazole pharmacology Pantoprazole CYP 2 C 19 Inactive Metabolite Center for INDIVIDUALIZED MEDICINE M. Whirl-Carrillo, E. M. Mc. Donagh, J. M. Hebert, L. Gong, K. Sangkuhl, C. F. Thorn, R. B. Altman and T. E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine"Clinical Pharmacology & Therapeutics (2012) 92(4): 414 -417. © 2012 MFMER | slide-32

Dutch Pharmacogenomic Working Group (DWPG) guidelines CYP 2 C 19 phenotype Recommendations Ultrarapid metabolizer H. Pylori treatment: Increase dose by 400%. All others: Consider dose increase of 400% All other phenotypes Standard dosing (20 mg / day) Center for INDIVIDUALIZED MEDICINE Accessed 21 Sept 2018, <www. pharmgkb. org> © 2012 MFMER | slide-33

Case 1: Plan for Judy Switch allopurinol to febuxostat Switch sertraline to fluoxetine PGx could explain why citalopram & escitalopram were not effective Increase dose of pantoprazole 40 mg daily 80 mg BID Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-34

Summary Pharmacogenomics is one of many variables in drug response Consider active drug vs. prodrug, phenoconversion Pharmacogenomics guidelines www. Pharm. GKB. org Case: Antidepressants, allopurinol, pantoprazole Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-36

Acknowledgements Center for Individualized Medicine (CIM) CIM Education Pharmacogenomic Task Force Ask Mayo Expert –Pharmacogenomics Patient video- Mayo Clinic Slides – R. Weinshilboum, MD; T. Curry, MD, Ph. D; W. Nicholson, MD, Pharm. D; P. Caraballo, MD; Caer Rohrer Vitek; Darcy Richardson; Kelly Fee-Schroeder; Tammy Mc. Allister Center for INDIVIDUALIZED MEDICINE © 2012 MFMER | slide-37