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

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

3. 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?

4. 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)

5. 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

6. 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 National Vital Statistics Reports. 2017; 66(6):1-73.

7. 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 Sep;52(9):829-37

9. 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)

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

11. Three domains of pharmacogenomics effects1
Hypersensitivity 2 3
Efficacy
Toxicity
Not universal icons

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

13. 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):

14. 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

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

16. What we know vs. what we don’t
509 drug labels with genetic information
100 drugs with dosing guidelines
PharmGKB. 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):

17. Common PGx Panel test report format styles

18. 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

19. 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

20. PGx hypersensitivity example

21. 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 Feb;93(2):153-8.

22. Allopurinol & HLA-B*58:01 Severe cutaneous adverse reaction (SCAR)
0.1% % 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:
Hershfield MS, et al. Clinical Pharmacogenomics Implementation Consortium (CPIC) Guidelines for Human
Leukocyte Antigen B (HLA-B) Genotype and Allopurinol Dosing. Clin Pharmacol Ther Feb;93(2):153-8.

23. 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 Jan;99(1):36-7.

24. 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 Jan;99(1):36-7.

25. PGx Case examples

26. 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

29. 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?

30. Pharmacogenomics resources
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

31. 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):

32. 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):

33. 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 Ask Mayo Expert updated in Feb 2017.
Accessed 21 Sept 2018,<

34. 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

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

36. 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
Case: Antidepressants, allopurinol, pantoprazole

37. 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

38. QUESTIONS?