1. Pharmacogenomics Dosing Drugs Based on Your Genes
Emily Holm, PharmD, BCACP
MN Academy of Physician Assistants
May 11th, 2018
Talk about why I am giving this talk.

2. Objectives: Define Pharmacogenomics (PGx)
Review Pharmacokinetics/Pharmacodynamics
Review Prodrugs vs Active Drugs
Learn Basic PGx Concepts
Review most common gene/drug interactions
Learn how PGx can be used in practice
Learn where to find additional PGx resources
Review simple and complex patient cases

3. THE BASICS!

4. Basic Concepts to Remember
Pharmaco:
genomics
kinetics
dynamics

5. genomics Pharmaco: Basic Concepts
Is the study of how a persons genes affect the body’s response to drugs
Definition is from Mayo Clinic Center for Individualized Medicine

6. What the body does to the drug (ADME)
Basic Concepts
Pharmaco:
kinetics
What the body does to the drug (ADME)
Absorption
Distribution
Metabolism
Elimination

7. Pharmaco: dynamics Basic Concepts The effect the drug has on the body
Genetic variant could make this have a “lack of effect” or toxicity

8. Types of Metabolizers (phenotypes)
Cytochrome P450 System
Family of enzymes in the liver responsible for the metabolism of most drugs
CYPs of Interest
CYP1A2
CYP2C9
CYP2C19
CYP2D6
CYP3A4
CYP3A5
Types of Metabolizers (phenotypes)
Ultra Rapid
Rapid
Normal
Intermediate
Poor
The RIGHT study from Mayo looked at 1000 patients PGx and found that 99% of the patients had a least one variant that would effect how certain drugs would be metabolized.

9. Prodrugs
Prodrug
Compound that has little or no activity on a desired pharmacological target, but is converted to an active, or more active form by metabolism
Few Examples:
Venlafaxine
Codeine
Tramadol
Clopidogrel
Tamoxifen

10. Drug Response Active Drug Prodrug Type of Metabolizer (Phenotype)
Ultra Rapid
Rapid
Normal
Intermediate
Poor
Lack of Drug Effect
Drug Accumulates
Drug Accumulates
Lack of Drug Effect

11. Case E.B. is 45 year old female that presents to clinic for depression
Failed or had intolerance (GI upset) the following antidepressants:
Fluoxetine
Paroxetine
Bupropion
Nortriptyline
Provider starts Venlafaxine ER 37.5mg daily
Two weeks later, patient reports symptoms have not improved so the provider increases the dose to 75mg daily.
Two weeks, patient returns to clinic with no improvement

12. Case What is the cost? Provider decides to order PGx
How is it collected?
Buccal swab
Blood sample
Saliva sample
What is the cost?
Historically, $2000-$3000
Starting at the beginning of April 2017 prices dropped
$250
Dropped

13. Case- PGx Results Gene (Metabolizing Enzyme) Genotype Phenotype CYP2D6
*4/*4
Poor
SLCO1B1
*1/*5
Increased Risk
HLA-B*5801
Negative
Normal Risk
CYP1A2
Multiple Variations
Normal
CYP2C9
*1/*1
CYP2C19
*1/*2
Intermediate
VKORC1
-1639 GA
Intermediate Sensitivity
CYP3A4
CYP3A5
*3/*3
Genotype = variant
Phenotype is the trait

14. PGx Results Patient is poor CYP2D6 metabolizer
Venlafaxine is a prodrug
Drug Accumulates
Patient not be able to metabolize venlafaxine into the active form, therefore the drug will not be effective.
Talk about the other intolerances to paroxetine, fluoxetine, nortriptyline, bupropion.

15. Desvenlafaxine (Active metabolite of venlafaxine)
Plan
Switch venlafaxine to an antidepressant that is not metabolized by CYP2D6
Escitalopram (CYP2C19)
Citalopram (CYP2C19)
Sertraline (CYP2C19)
Desvenlafaxine (Active metabolite of venlafaxine)
If you want to do a PA.

16. How is PGx useful? Eliminates Medication Trial and Error
Avoids Therapeutic Failure
Decreases Medication Adverse Effects
Decreases Cost
Individualizes Patient Care

17. Pertain To All Medications Explain Drug Allergies
PGx DOES NOT
Pertain To All Medications
Explain Drug Allergies
Explain Drug-Drug Interactions
Explain Drug-Food Interactions
Still have to look at the patient as a whole.
Still need to look at renal function/hepatic function
Drug Pharmacology/Drug-Drug interactions/then PGx. Ask yourself.. Does this make sense?

18. Important Drug-Gene Pairs
allopurinol
HLA-B*5801
warfarin
CYP2C9/ VKORC1
clopidogrel, citalopram, escitalopram, sertraline
CYP2C19
codeine, tramadol, tamoxifen, venlafaxine, fluoxetine, paroxetine
CYP2D6
simvastatin
SLCO1B1
This list is not all inclusive

19. HLA-B*5801 and Allopurinol
HLA-B*5801 is linked to life-threatening cutaneous adverse reactions (SCAR) in some populations (Stevens-Johnson Syndrome)
American College of Rheumatology published updated guidelines in 2012 for the management of gout, including consideration of HLA-B*5801 testing prior to the initiation of allopurinol in select populations (Asian descent).
If patient is found to carry the HLA-B*5801 allele, the use of allopurinol is considered contraindicated
Frequency in Asian populations is 6%-12%.
Universal HLA-B*58:01 screening prior to prescribing allopurinol is not recommended, based on current evidence that Caucasians (HLA-B*58:01 allele frequency of ~2%) are at much lower risk than Asian populations (HLA-B*58:01 allele frequency of ~6 to 12%), in part due to differences in allele frequency
AME
Accessed 03/28/17

20. HLA-B*5801 and Allopurinol Recommendations:
Alternative options if allopurinol is contraindicated:
Treatment of gout
Probenecid
Uloric® (febuxostat)

21. CYP2C9/VKORC1 and Warfarin
Warfarin metabolism is influenced by variants in the CYP2C9 and VKORC1 genes
Patients with non-wild type CYP2C9 alleles may have altered metabolism
Warfarin decreases vitamin K-dependent clotting factors by inhibiting the VKOR enzyme
Dosage requirements
25% lower in the GA genotype
50% lower in the AA genotype

22. CYP2C9/VKORC1 and Warfarin Recommendations:
Dosing Table for starting warfarin (Adapted from Ask Mayo Expert)
CYP2C9
VKORC1
*1/*1
*1/*2
*1/*3
*2/*2
*2/*3
*3/*3 GG
5 to 7mg
3 to 4mg
0.5 to 2mg GA AA

23. Case- PGx Results

24. Case CYP2C9 is normal - *1/*1 VKORC1 is GA: Intermediate sensitivity
Routine genotyping prior to initiation of warfarin therapy is not currently recommended. This is in keeping with the most recent Chest 2012 guidelines on anticoagulant management. However, if genotype test results are available, they may assist in guiding warfarin initiation.

25. CYP2C19 and Clopidogrel Clopidogrel is a prodrug
Effectiveness is dependent on metabolism to active metabolite by CYP2C19
Poor metabolizers with acute coronary syndrome or those undergoing percutaneous coronary intervention display higher cardiovascular event rates when treated with clopidogrel at normal doses than patients who are normal metabolizer
CYP2C19 loss-of-function alleles appear to be associated with higher rates of recurrent cardiovascular events in patients receiving clopidogrel.

26. CYP2C19 and Clopidogrel Recommendations:
Alternative medications should be considered for patient who are intermediate to poor metabolizers
Brilinta® (ticagrelor)
Effient® (prasugrel)
Preemptive PGx is not currently recommended by the ACCF/AHA
TAILOR-PCI trial
Studying if CYP2C19 preemptive genotyping in patients undergoing PCI improves outcomes
Tye – KA- grel- or
Finding 30% of patients have genetic variation that interferes with CYP2C19 metabolism. I am one of these people.

27. CYP2C19 and Citalopram/Escitalopram/Sertraline
Citalopram, escitalopram, sertraline are active drugs
Primarily metabolized via CYP2C19
Intermediate to Poor metabolizers have an increased risk of adverse drug events due to drug accumulation

28. CYP2C19 and Citalopram/Escitalopram/Sertraline Recommendations
Alternative medications include:
Fluoxetine
Venlafaxine
Duloxetine
Bupropion
Paroxetine
Fluvoxamine
Nortriptyline
Mirtazapine *
Consultation with a pharmacist or psychiatrist is warranted for patients who are poor or poor to intermediate metabolizers for both CYP2D6 and CYP2C19

29. CYP2D6 and Antidepressants
Intermediate to Poor Metabolizers
Increase risk of side effects with
Fluoxetine
Fluvoxamine (can decrease dose by 25%-50% if needed)
Paroxetine (can decrease dose by 50% if needed)
Increase risk of treatment failure
Venlafaxine
Recommendations
Choose antidepressant not metabolized by 2D6
Citalopram, escitalopram, sertraline
CYP2D6 is reasonable for the metabolism of about 25% of all drugs.
Side effects – GI upset, serotonin syndrome or QTc prolongation..
Consultation with a pharmacist or psychiatrist is warranted for patients who are poor or poor to intermediate metabolizers for both CYP2D6 and CYP2C19

30. CYP2D6 and Analgesics Both Tramadol and Codeine are prodrugs
Metabolized into active forms by CYP2D6
Tramadol to O-desmethyltramadol
Codeine to morphine
Types of metabolizers at risk
Ultra Rapid (risk of toxicity)
Rapid (risk of toxicity)
Poor (reduced efficacy)

31. CYP2D6 and Analgesics Recommendations
Alternatives
Hydrocodone/APAP
Oxycodone
Both are also substrates of CYP2D6, but it’s a minor pathway
Morphine
Hydromorphone
Fentanyl
If appropriate

32. CYP2D6 and Tamoxifen Tamoxifen
SERM used for the prevention and treatment of ER+ breast cancer
Tamoxifen is a prodrug and is metabolized to active form (endoxifen) by CYP2D6
Types of Metabolizers at risk
Intermediate – Avoid medications that inhibit CYP2D6
Poor to Intermediate (limited therapeutic response)
Poor (possible therapeutic failure)
Tamoxifen is a selective estrogen receptor modulator approved by the U.S. Food and Drug Administration for the prevention and treatment of estrogen receptor-positive breast cancer.
Tamoxifen is a prodrug. Patients who have decreased activity of the liver enzyme CYP2D6 are less effective at converting tamoxifen into the active metabolite endoxifen. Women who have a poor, poor to intermediate, or intermediate ability to metabolize tamoxifen via CYP2D6 may have a limited therapeutic response, depending on the setting in which tamoxifen is administered.

33. CYP2D6 and Tamoxifen Recommendations
Intermediate metabolizer
Usual tamoxifen dosing, however AVOID medications that inhibit CYP2D6
Diphenhydramine, hydroxyzine, chlorpheniramine
Celecoxib
Bupropion*, duloxetine, fluoxetine*, paroxetine*, sertraline
Poor to intermediate OR Poor
Should be switched to Aromatase Inhibitor
Anastrozole
Exemestane
Letrozole
Ex –e- MES- tane
Patients who are unable to tolerate an aromatase inhibitor or have other contraindications for an aromatase inhibitor should still be treated with tamoxifen. However, these patients may have a limited therapeutic response, depending on the setting and duration of tamoxifen administration.
Other measures considered investigational include increasing tamoxifen dosage from 20 mg/day to 40 mg/day in women who are poor CYP2D6 metabolizers, which has been shown to increase endoxifen concentrations
* Denotes Strong Inhibitors

34. SLCO1B1 and Simvastatin
Statin-induced myopathies are difficult to predict
Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine discovered that the SLCO1B1 CC and TC genotypes were linked with a higher risk of statin-induced myopathy when compared with the TT (normal) genotype in patients taking simvastatin (Zocor) 40 or 80 mg daily.
The SLCO1B1 gene influences the extent of the drug's hepatic uptake by its transporter (OATP1B1) and its serum concentration.

35. SLCO1B1 and Simvastatin Recommendations
Genotypes at increase risk of myopathy CC TC
Alternative statin options
Atorvastatin
Pravastatin
Rosuvastatin
If simvastatin must used, the max dose recommended is 20mg/day

36. Complex Case
F.H. is a 55 year old female who presents to clinic with chief complaint of musculoskeletal pain.
She has been taking APAP 1000mg 4xday and IBU 600mg TID with no relief

37. Complex Case Type 2 DM STEMI (10/2016) Hypertension Hyperlipidemia
Metformin 1000mg 2xday
Type 2 DM
Clopidogrel 75mg daily
STEMI (10/2016)
Lisinopril 20mg daily
Metoprolol XL 100mg daily
Hypertension
Simvastatin 40mg
Hyperlipidemia
Acetaminophen 1000mg 4xday
Ibuprofen 600mg 3xday
Pain
Pantoprazole 40mg daily
Acid Reflux

38. Complex Case Vitals BP: 118/85 mmHg HR: 46 bpm A1c: 6.8% Scr: 0.8
AST: 13
ALT: 20

39. Complex Case Tramadol 50mg Q6H is prescribed
Patient returns after one week with continuing pain and no response to tramadol
Patient has preemptive PGx in her chart
Discuss recommendations based on patients presentation, medications, and PGx results

40. Complex Case- Questions to ask yourself
Look at the PGx report and ask yourself…..
Are the drug(s) in question an active drugs or a prodrugs?
What are the metabolic pathway(s) of the drug(s)?
Does this make sense?

41. Complex Case- PGx Results
Gene (Metabolizing Enzyme)
Genotype
Phenotype
CYP2D6
*4/*4
Poor
SLCO1B1
*1/*5
Increased Risk
HLA-B*5801
Negative
Normal Risk
CYP1A2
Multiple Variations
Normal
CYP2C9
*1/*1
CYP2C19
*1/*2
Intermediate
VKORC1
-1639 AA
High Warfarin Sensitivity
CYP3A4
CYP3A5
*3/*3
Extensive = normal

42. Complex Case Discussion
Poor CYP2D6 Metabolizer
Tramadol is a prodrug, therefore lack of efficacy
Metoprolol is metabolized by CYP2D6, possible drug accumulation (HR is 46 bpm
SLCO1B1 increased risk of myopathy with simvastatin
Intermediate CYP2C19 Metabolizer
Clopidogrel is a prodrug, therefore lack of efficacy
Bonus: Pantoprazole inhibits CYP2C19, therefore this may additionally decrease clopidogrel activity*

43. Complex Case Plan D/C Tramadol due to ineffectiveness
Consider Oxycodone or Hydrocodone/APAP for pain
Decrease metoprolol XL to 50mg due to bradycardia
Switch simvastatin to atorvastatin/pravastatin/rosuvastatin
Consult Cardiology to switch clopidogrel to Effient® (prasugrel) or Brilinta® (ticagrelor)
Could lower the dose of simvastatin if needed

44. Patient Video

45. Where to find additional resources
CPIC Guidelines
PharmGKB
OneOme CYP Inducers and Inhibitors Table

46. Summary PGx can help eliminate medication trial and error
PGx can help avoid therapeutic failures
PGx can decrease medication side effects
PGx can help decrease healthcare costs
PGx individualizes patient care

47. Summary

48. Questions?
Thank you!

49. Bibliography
Li XQ, Andersson TB, Ahlstrom M, et al, “Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metab Dispos, 2004, 32:821-7. 
“HLA-B*5801 and Allopurinol (pharmacogenomics)." AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar
“Warfarin and CYP2C9 and VKORC1(pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“CYP2C19 and clopidogrel (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“Antidepressant Medication and Pharmacogenomics.” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“Tramadol and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“Codeine and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“ Tamoxifen and CYP2D6 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2017
“Simvastatin and SLCO1B1 (pharmacogenomics).” AskMayoExpert. Mayo Clinic, 19 Sept Web. 30 Mar. 2107
Huttunen, Kristiina M., Hannu Raunio, and Jarkko Rautio. "Prodrugs-from Serendipity to Rational Design." Pharmacological Reviews 63.3 (2011): Print