WHMS PGx Presentation. For more information, please go to: www.getmydnatest.org

1. Pharmacogenetics &
Your Medical Practice
Presenters:
Tom Ashlock, MD
Morris Burgess, PharmD
Luis Martinez, MD
Phil Tagariello, PharmD

2. What Your Patients are starting to see…
MAYO CLINIC INTRODUCTION to PHARMACOGENOMICS

3. As Seen On TV… What Your Patients See…

4. There is a new potential threat on the horizon for Physicians – and
the UCLA Journal of Law and Business has already published an
extensive article about it… Pharmacogenetic testing is a tool
currently available to assist you in your practice. Not using it
proactively can and likely will have an adverse effect on your
practice in the form of LIABILITY…
Eliminate trial and error:
“Right Drug, Right Dose, Right Indication, Right Patient, Right
Time”
• Eliminate “One Size Fits All” medication management
• Enhance Patient Care
• Enhance Patient Satisfaction
• Enhance Compliance
• Enhance Patient Confidence.
• Risk Management: Reduce liability to physician
Why Should Physicians Test their Patients?

5. FDA has posted 130 Black Box Warnings where manufacturers recommend pharmacogenomics testing
prior to or soon after initiation of therapy. Of those, over 100 drugs require pharmacogenetic testing
prior to prescribing, or it is highly recommended..
http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm

6. Pharmacogenetic Testing: A Reality TODAY
“Pharmacogenetic testing eventually can lead to an overall decrease in the
cost of health care…”
Physicians “should consider pharmacogenomics information an additional
piece of information when selecting drug therapy. We should also encourage
health care systems and interested providers to be early adopters…”
“Some would argue that, once we have the information, we have an
obligation to use it, just as we use other information in our clinical decision-
making.”
Overcoming Barriers to Using Pharmacogenomics in Practice
Kathryn Teng, MD
Department of Internal Medicine, Cleveland Clinic
From the website of the American Medical Association
http://www.ama-assn.org/ama/pub/physician-resources/medical-science/genetics-molecular-medicine/current-
topics/pharmacogenomics.page?
In 2013 the following institutions implemented PGx testing: Cornell,
Columbia, Georgetown, Harvard, Mayo Clinic, Scripps, Stanford, Vanderbilt…
to name a few.

7. Why Should We Care about Pharmacogenetics Testing?
• There are over 2.2 million+ avoidable ADR hospitalizations per year
• There are over 106,000 avoidable ADR deaths per year. That equates to
1 avoidable death every 5 minutes!
• FDA report states in excess of $136+ billion in avoidable annual cost for ADRs
• Additionally… over 350,000 Nursing Home ADRs per year
• Study concluded … of 3695 hospitalized patient episodes for ADRs, over half of them
were definitely avoidable
• The more drugs a patient is taking, the more chance of an ADR
• The average Medicare patient takes 5-8 drugs with some as high as 20+ drugs per day
• Over 50% of Nursing Home patients take 5+ drugs and placed on at least one psychiatric drug
within 2 weeks
• Patients taking over 11 drugs have a 96% chance of and ADR
Pharmacogenetics Testing can significantly reduce these statistics, yet we are
unnecessarily subjecting our patients to avoidable ADRs… and even deaths

8. Drug Metabolizing Phenotype
•Ultra Rapid Metabolizers (UM)
•Increased enzyme
•Extensive Metabolizers (EM)
•Normal
•Intermediate Metabolizers (IM)
•Impaired
•Poor Metabolizers (PM)
•Non functional

9. Major CYP450 Isoforms
1. A2 6. 2D6
2. 2B6 7. 2E1
3. 2C8 8. 3A4
4. 2C19 9. 3A5
5. 2C9 10. 3A7

10. • Inhibitor
• A substrate(drug) that slows down or “inhibits” the metabolism of
other substrates
• Inducer
• A substrate that increases the elimination of other substrates
• Prodrug
• A substrate that is biologically inactive in its original (parent) form.
These drugs must be metabolized (“activated”)before they work
in the body and produce their desired effect
Definition of Terms Used Regarding Drug Properties

11. Pharmacogenomic testing: Relevance in medical practice
Why drugs work in some patients but not in others
Cleveland Clinic Journal of Medicine, Volume 78, Number 4, April 2011

12. Case Study 1: Codeine
30 year old woman gave birth; post episiotomy was given codeine for pain. Breast fed
healthy infant; at 13 days infant died. Post mortem autopsy revealed morphine overdose of
infant.
How would genetic testing help patient and physician?
Genotyping of patient’s CYP2D6 gene prior to prescribing codeine would have revealed
patient was an ultra-rapid metabolizer. Armed with this knowledge, patient’s physician would
have prescribed a different analgesic; and saved patient’s infant’s life
Pain Medicine News: Genetic Testing in Pain Medicine April 2013
“In the classic “nature versus nurture” scenario, investigators use twin pairs…looked at pain
conditions and concluded that migraines have a 39% to 58% genetic contribution, low back
pain carries a 21% to 67% contribution.”
In that same article they state… “patients taking 8 drugs…they calculated a potential of
476 drug interactions in 63% of the patients.”
10% Caucasians are ultra-rapid metabolizers of codeine. Another 5% of African
Americans, Asians and Hispanics are ultra-rapid metabolizers. “Only 1% of patients
were aware of the potential for drug-drug, or drug-gene interactions.”
“Only 58% of patients receive relief from pain medications with the first attempt” at
getting it right. (Peter D. Hart Research Associates)

13. •Case Study 2: Clopidogrel
JM, a 58 year-old man recently had an acute MI. To prevent ischemic events, JM’s physician
recommends antiplatelet therapy and prescribes Clopidogrel. Six months later, JM suffered
another acute MI, and his physician suspects that patient has been non-adherent, or
alternatively, that Clopidogrel therapy may have been ineffective.
How would genetic testing help JM and his physician?
Determining JM’s CYP2C19 genotype may reveal that he carries a variant that diminishes the
antiplatelet effect on Clopidogrel. If this were the case, alternative anti-platelet therapies may
have been considered, reducing the chance that JM would suffer a second cardiac event.
Patients with reduced function alleles have a 3.5 – 8 times greater risk for major adverse
cardiovascular events, with greater risk in poor metaboloizers (Tobassome, MD – Genetic
Determinants of Response to Clopidogrel and Cardiovascular Events).
NOTE: FDA has posted a warning that diminished effectiveness in poor metabolizers
may cause lack of efficacy and place patient at great risk.

14. Case Study 3: Warfarin
ML, a 65 year-old woman diagnosed with atrial fibrillation. To reduce the risk of stroke and
other thrombotic events, ML’s physician recommends Warfarin therapy. To estimate the
initial dose, ML’s clinical characteristics were considered (age, sex, weight, diet). However,
ML will need to return to the clinic every day for INR monitoring until a stable dose is
determined, and then every few weeks thereafter for maintenance monitoring.
How would genetic testing help ML and her physician?
Determination of ML’s CYP2C9 and VKORC1 genotype would reveal whether she carries
any variations that alter her ability to metabolize and respond to Warfarin. Knowing about
any gene variations before initiating therapy allows for more accurate initial dosing and
faster INR stabilization, and can reduce the risk of bleeding or clotting events.
NOTE:
JACC Journal: Warfarin Genotyping Reduces Hospitalization Rates June 2010 (Medco-Mayo Warfarin
Effectiveness Study)
Reveals that there was a “43% lower risk of hospitalization for bleeding or thromboembolism in patients who
were genotyped.”
Pharmacogenetics testing is applicable to 70-75% of patients not in controlled anticoagulation centers.
Testing reduced between 4,500 and 22,000 serious bleeding events annually.
Pharmacogenetic testing is now required by FDA

15. Case Study 4: Clonidine and Fluoxetine
9 year old boy with ADHD placed on Clonidine and Fluoxetine develops symptoms of low-
grade fever, in-co-ordination and seizures. Boy went into status epilepticus and died. The boy
could not metabolize Prozac, and he had built up very toxic levels before anyone recognized
it.
Mrazek in Psychiatric Times states that “some patients still die even when medication
is stopped because some patients have limited metabolic capacity.”
How would pharmacogenetic testing help this patient and physician?
Physician would have known that patient was a poor metabolizer of CYP2C19 and
chosen another therapeutic regimen that was not metabolized through that pathway
NOTE: FDA reports 30 approved drugs psychiatric drugs with pharmacogenetic testing
information on their labels.
Mrazek, in Psychiatric Times, “recommended increased clinician education…and
translation of laboratory test results into actionable prescribing decisions for specific
drugs including pharmacogenetic information on electronic medical records.”
In their JAMA article, “Mrazek predicted that it won’t be too long before diagnostic and
treatment guidelines for psychiatric disorders recommend pharmacogenomics testing
as part of the initial workup.”

16. “Liability is likely to be a major driver for the future direction and
implementation of personalized medicine, spurring the adoption of
genetic tests and other pharmacogenomic technologies…
… liability will often be both unpredictable and influential in
changing medical practice. It is critical to anticipate and attempt to
prevent such liability risks in a proactive manner so to minimize
the disruptive impact that liability can cause.”
Physician Liability: The Next Big Thing for Personalized Medicine?
Gary E Marchant, Doug E Campos-Outcalt, Rachel A Lindor
Personalized Medicine. 2011;8(4):457-467.
Risk Management: Reduce liability to physician

17. Medical Malpractice: “Physicians could face liability for failure to test
patients… only 13% of the more than 10,000 physicians surveyed had ever
prescribed a pharmacogenomic test.”
“Pharmacogenomics will alter the way physicians practice medicine. As
physicians incorporate pharmacogenomic techniques in their practice,
patients will likely suffer fewer ADRs… however, pharmacogenomics will likely
be accompanied by (if not spurred on by) medical malpractice suits based on a
number of claims.”
Lack of Informed Consent: “…injured patients could sue under a theory of
informed consent… physician failed to disclose all pertinent information,
including risks, benefits, and alternatives,… they would have chosen a
different avenue of treatment.”
UCLA Journal of Law and Technology: Legal Issues Stemming from the
Advancement of Pharmagenomics

20. • Simple, Non invasive Buccal Swab
• Pediatrics: no diagnosis required (base-line for future drugs), OB: Medical Necessity Black Box Warning
• Medical Necessity only requires patient be on 2 meds (OTC or Script)
• Medicare fully covers PGx testing with no deductible and no copay.
• Most Third Party cover PGx testing subject to deductible/copay.
• Cash payors charged same as Medicare – currently about $1,000.
• One-time, lifetime test that will benefit the patient for life – unlike routine tests such as CBCs etc. that are
often ordered throughout a patient’s lifetime equating to much more than the one-time test.
• Lab offers “Friendly Billing Policy” - Lab DOES NOT call patient or send patient bill to collection or credit
bureau in the event Lab does not receive patient portion of the test. Billing questions handled by Lab.
• Lab assists patients in financial need.
• Physician may be eligible to bill at a “higher level of complexity” for an office visit. Eg: If physician
normally bills 99212 or 99213, he may choose to bill 99214 and increase reimbursement to his practice by
an average of $50. PGx testing qualifies for one of the requirements to be eligible for the higher rate of
billing. Physician should properly annotate patient office visit notes.
. Physician may bill for interpretation of PGx test with G0452, reimbursement to practice of approx. $20.
Some physicians successfully bill individually for each one of the 9 panels.
Ease of Testing, CPT Codes, Billing and Reimbursement

21. • Physicians use science to diagnose, but have had to use “trial and
error” in prescribing for therapeutic treatment. NOW, prescribers have
science to assist them in getting the right med for the right patient at
the right dosage – the first time.
• Enhance patient care, Enhance patient satisfaction, Enhance patient
compliance, Enhance patient confidence, Enhance patient outcome
• Receive “Private Consult” with PharmD on your patients before prescribing
• Risk Management: Reduce liability to physician
One Question Remains:
Now that you have reviewed the risks and benefits of implementing
Pharmacogenetics Testing into your Medical Practice:
Why Wouldn’t You Begin Testing Your Patients
Now?
Why Should Physicians Test their Patients?

22. Cardiovascular pharmacogenomics: current status, future prospects
Anderson JL, Carlquist JF, Horne BD, Muhlestein JB
J Cardiovasc Pharmacol Ther 2003;8(1):71-83
Pharmacogenomics — Drug disposition, drug targets, and side effects
Evans, WE, and McLeod, HL
New England Journal of Medicine 2003; 348:538-549
Cancer pharmacogenomics: current and future applications
Watters JW, McLeod HL
Biochim Biophys Acta 2003 Mar 17;1603(2):99-111
Pharmacogenomics study of statin therapy and cholesterol reduction
Chasman DI, et al.
Journal of the American Medical Association 2004; 291(23) 2821-2827.
Role of pharmacogenomics in individualizing treatment with SSRIs
Mancama D, Kerwin RW
CNS Drugs 2003;17(3):143-51
Partial List of References for Clinical
Applications