Pharmacogenomics in the Modern Healthcare Setting Jessica Wright, PharmD, BCACP Pharmacogenomics Medication Therapy Management Pharmacist Center for Individualized Medicine Mayo Clinic

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

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?

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 Review components-- > print off handouts for diff pgx tests (kailos, gene Dx)

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

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 Murphy SL, et al. Deaths: Final Data for 2015. National Vital Statistics Reports. 2017; 66(6):1-73.

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

Factors Related to Drug Responses Intrinsic factors: Age, gender Race/ethnicity Disease states, organ dysfunctions Genetics Physiological changes: Pregnancy, lactation Extrinsic factors: Smoking/EtOH Diet Concomitant medications Medication compliance Huang SM, Goodsaid F, Rahman A, et el. Toxicology Mechanisms and Methods. 2006;(16) 89-99.

What is pharmacogenomics? Study of genetic variations that influence individual response to drugs Same Condition No Response Desired Response Toxic Side Effects

Three domains of pharmacogenomics effects 1 Hypersensitivity 2 3 Efficacy Toxicity Not universal icons

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

Metabolizer Status may impact drugs differently Active Drug Active  Inactive Poor metabolizer = too much drug Metoprolol is metabolized by CYP2D6 then eliminated Prodrug Inactive  Active Poor metabolizer = too little drug Tamoxifen is converted to its active metabolite by CYP2D6 M. Whirl-Carrillo, E.M. McDonagh, 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.

Alteration of Metabolizer Status In addition to genetic variation, other drugs/foods can impact drug metabolism Inducer: increases enzyme activity Inhibitor: decreases enzyme activity Horn JR. (2018) Basic and Clinical Pharmacology. Retrieved from https://accessmedicine.mhmedical.com/content.aspx?bookid=2249&sectionid=175226529#1148443525

Nomenclature Nelson, DR, Pharmacogenetics 1996; 6. 1–42

What we know vs. what we don’t 509 drug labels with genetic information 100 drugs with dosing guidelines PharmGKB. www.pharmgkb.org Accessed 21 Sep 2018. M. Whirl-Carrillo, E.M. McDonagh, 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.

Common PGx Panel test report format styles

Stoplight format Red: Major gene-drug interaction Yellow: Moderate gene- drug interaction Green: Minimal or no gene-drug interaction - OR - Major -Drug A Moderate -Drug B & C Minimal / None - Drug D, E & F

Drug-specific format Example PGx Report 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

PGx hypersensitivity example

HLA-B*58:01 & Allopurinol T-cell receptor HLA-B*58:01 T-cell Keratinocyte Reference = CPIC 2013 guidelines 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.

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 Stevens Johnsons Syndrome (SJS) Toxic epidermic necrolysis (TEN) Drug reaction with eosinophilia and systemic symptoms (DRESS) Photo courtesy of: http://blogs.bmj.com/bmj/files/2012/02/toxic_epidermal_necrolysis.jpg 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.

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 Reference = CPIC supplemental guideline 2015 for allopurinol. Supplement v 2.0. 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.

Allopurinol take home points Asian descent + starting allopurinol  Screen for HLA-B*58:01 HLA-B*58:01 positive  Avoid allopurinol Negative HLA-B*58:01 doesn’t exclude possibility of SCAR Especially in Caucasians Other possible markers identified HLA-A*33:03 HLA-C*03:02 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.

PGx Case examples

Case 1: Judy Initial Presentation: Medications: 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 200mg daily x 4 months with only minimal improvement. Due to multiple inefficacies, pharmacogenomics testing ordered Medications: Aspirin, allopurinol (started 3 days ago), sertraline, pantoprazole

Case 1: Drug-Gene Interactions Medication Gene Phenotype Sertraline CYP2C19 Ultrarapid metabolizer Allopurinol HLA-B*58:01 Positive Citalopram Escitalopram Sertraline – intermediate - normal  what activity level is this?

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

CPIC guidelines: SSRIs Phenotype Citalopram & escitalopram recommendation Sertraline recommendation Ultrarapid Consider an alternative drug not metabolized by CYP2C19 Initiate with recommended starting dose. If patient doesn’t respond to recommended maintenance dosing, consider an alternative drug not predominantly metabolized by CYP2C19 Normal or Intermediate Standard dosing recommended Poor metabolizer Consider a 50% reduction of starting dose and titrate to response or select an alternative drug. M. Whirl-Carrillo, E.M. McDonagh, 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.

Pantoprazole pharmacology CYP2C19 Inactive Metabolite M. Whirl-Carrillo, E.M. McDonagh, 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.

Dutch Pharmacogenomic Working Group (DWPG) guidelines CYP2C19 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) CPIC guidelines updated in 2018. Ask Mayo Expert updated in Feb 2017. Accessed 21 Sept 2018,<www.pharmgkb.org>

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 40mg daily  80mg BID

“Could Pharmacogenomics help my patient?” Karen’s Story Youtube link 2 min video

Pharmacogenomics is one of many variables in drug response Summary Pharmacogenomics is one of many variables in drug response Consider active drug vs. prodrug, phenoconversion Pharmacogenomics guidelines www.PharmGKB.org Case: Antidepressants, allopurinol, pantoprazole

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, PhD; W. Nicholson, MD, PharmD; P. Caraballo, MD; Caer Rohrer Vitek; Darcy Richardson; Kelly Fee-Schroeder; Tammy McAllister CIM Education Program staff Caer Vitek Darcy Richardson Kelly Fee-Schroeder

QUESTIONS?