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Copyright 2019 PCA Pharmacy.
Disclosure of Commercial Interests
I have not consulted for and do not have financial interest in any organizations related to Pharmacogenomics.
Rob Leffler is the Vice President of Clinical Services for PCA Pharmacy
PCA Pharmacy is a provider of pharmacy services for Long-Term Care Facilities.
Copyright 2019 PCA Pharmacy.
Rob Leffler, R.Ph.March 18, 2019
Pharmacogenomics and Improving Patient Care
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Objectives• Identify what pharmacogenomic testing is and how it can be utilized
• Describe how pharmacogenetic tests can inform prescribing decisions
• Discuss pros and cons of pharmacogenetic testing
• Identify patients that could benefit from pharmacogenomic testing
• Explain why pharmacogenomic testing is valuable to another healthcare professional
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THANK YOU!• Dr. David Bright, PharmD, BCACP; Associate Professor at Ferris State University
College of Pharmacy
• Dr. David Kisor, BS, PharmD; Professor and Chair of Pharmaceutical Sciences; Director of Master of Science in Pharmacogenomics at Manchester University
• Dr. Thomas Smith, Pharm.D., BCPP; Assistant Professor of Pharmacy Practice at Manchester University College of Pharmacy
• Dr Shannon Zandy, Pharm.D., Ph.D., Medical Science Liaison at Myriad Genetics
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One Drug Does Not Fit All
5Spear (2001) Trends Mol Medicine 7(5):201‐4.
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Precision Medicine or Personalized Medicine• 2015 State of the Union Address announced the launch of the
Precision Medicine Initiative• Isn’t medicine being personalized already?
• Doses and drugs are selected based on other diagnoses, kidney function, etc.
• Are therapeutic responses always predictable?• Are there still unanticipated side effects?• Genes can correlate to how well or even whether drugs work
https://www.nih.gov/precision‐medicine‐initiative‐cohort‐program. Accessed 10/4/2016
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Personalized Medicine• Provide the “right patient with
the right drug at the right dose at the right time”
• Genetic or protein biomarkers that may predict medication response or adverse effects
• Pharmacogenomics• Subset of personalized medicine
currently implemented in certain practice settings1
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https://www.genome.gov/27530645/faq‐about‐pharmacogenomics/1Relling and Evans (2015) Nature 526(7573):343‐50.
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Precision Medicine or Personalized Medicine
• Drugs are designed for the “average patient”• Drugs helped some people but not others
• We ARE customizing drug selection based on personalized factors such as genetics, environment and lifestyle
• We are NOT creating custom medications for individual patients• Ex: Huge advances have been made in the treatment of cancer
• This initiative is constantly expanding to other drugs
Kisor DF, et al. Pharmacogenetics, Kinetics, and Dynamics for Personalized Medicine. JBL 2013.
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Example:
•Cystic Fibrosis is the most commonly inherited disease in Caucasians• Affects 1 in 3,000 newborns• Carrier frequency is 1 in 25• Certain cases are caused by a specific genetic
mutation of CFTR modulators• This mutation can be treated with drugs:
ivacaftor (Kalydeco) & lumacaftor/ivacaftor (Orkambi)
https://www.ncbi.nlm.nih.gov/pubmed/12143267https://www.ncbi.nlm.nih.gov/pubmed/19780730. Accessed 10/4/16
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PGx/PGX and PGt
• Genomics• Genome – Study of the entire DNA sequence
• Pharmacogenomics (PGx or PGX)• Study of how a person’s genes affect a person’s response to particular
drugs• More general term for the interface of genomics and therapeutics
• Pharmacogenetics (PGt)• Study of how one gene affects a person’s response to a particular drug
https://ghr.nlm.nih.gov/handbook/precisionmedicine/precisionvspersonalized
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Genotype and Phenotype
• Genotype: Genetic coding • Example: CYP2C19 GG (*1/*1)
• Phenotype: Expression of genetic coding• Example: extensive (normal) metabolizer
• Other Genotypes• *2 - G is replaced by A• *17 - C is replaced by T
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More Definitions
• Single nucleotide polymorphism (SNP, pronounced “SNIP”): A variant DNA sequence in which a single nucleotide has been replaced by another base• cytosine (C), thymine (T), adenine (A), guanine (G)
• These changes can impact transporters, receptors, metabolizing enzymes, etc.
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Drug Metabolizing Enzymes• In pharmacogenomics, we are often concerned with SNPs in drug metabolizing enzymes in the liver• Examples: CYP450 2C9, 2C19, 2D6
•Many drugs are metabolized by the liver• More activity• Less activity
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CYP2C19 SNPs• Common CYP2C19 alleles:
• *1 (standard function)• *2, *3 (loss of function; no function)• *17 (gain of function)
• One allele from each parent• Combinations of alleles must be considered to understand CYP
function (Phenotype)• *17/*17 (ultra rapid metabolizer/UM)• *1/*1 (normal (extensive) metabolizer/EM)• *1/*2 ; *2/*17 (intermediate metabolizer/IM)• *2/*2 (poor metabolizer/PM)
Scott SA, et al. Clin Pharmacol Ther 2013;94(3):317‐23.
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CYP2C19 SNPs
• European/African ancestry: • ~30% express a *2 allele,
3-4% as *2/*2• Oceanian ancestry:
• ~61% express a *2 allele• Implications for drugs
activated or inactivated by CYP2C19
Scott SA, et al. Clin Pharmacol Ther 2013;94(3):317‐23.Johnson JA, et al. Clin Pharmacol Ther 2012;91(5):774‐6.
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Why Are We Concerned with Geriatrics?• Treating geriatric patients can be difficult due to polypharmacy
• About 40% of geriatric patients are on ≥5 Rx medications1
• Long-term care residents take an average of 8.5 prescriptions on a regular basis2
• The prevalence and severity of adverse drug reactions (ADRs) is increased in older people• 5-10% of hospital admissions amongst older people are related to ADRs3
• Older people are 4x more likely to be admitted to hospital because of ADR (16.6% vs. 4.1%) and are more likely to have preventable ADRs (88% vs. 24%)4
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1Qato (2008) JAMA 300(24):2867‐78. 2Stevenson (2014) Med Care 52(10):884‐90. 3Davies (2015) Br J Clin Pharmacol 80(4): 796‐807. 4Beijer (2002) Pharm World Sci 24(2):46‐54.
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Why Are Adverse Drug Reactions Increased?
• Comorbidities1,2
• Polypharmacy2
• Physiologic Changes2,3
• Pharmacokinetic changes• Pharmacodynamic changes
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Prescription drug use in the past 30 days, by number of drugs taken and age: United States 2007‐2010.4
1Nobili (2011) J Comorb 1:28‐44. 2Davies (2015) Br J Clin Pharmacol 80(4): 796‐807. 3Brunton (2018) Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed4Katzung (2012) Basic and Clinical Pharmacology, 12th ed
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Pharmacokinetic Changes in the Elderly
1Jansen (2012) Scientifica (Cairo) 2012:723678 2Klotz (2009) Drug Metab Rev 41(2):67‐76. 3Tijiri (2013) World J Gastroenterol 19(46):8459‐67. 4Sotaniemi (1997) Clin Pharm Ther 61(3):331‐9. 5Katzung (2012) Basic and Clinical Pharmacology, 12th ed
MISD.187.01.176
Absorption may be delayed, but bioavailability is largely unchanged1
Drugs with high 1st pass metabolism are an exception2
Fat ↑, highly lipophilic drugs may have longer half‐livesWater ↓, hydrophilic drugs may have higher concentra ons2
Absorption
Distribution
Metabolism
Phase I: CYP450 enzyme ac vity reported ↓ in elderly although conflic ng reports3
One study found patients age >70 CYP450 activity reduced by ~30%4
Phase II: Mostly conserved in the elderly population2
ExcretionReduction in kidney size, blood flow, nephron function, and filtration rate can lead to a decrease in elimination of water‐soluble drugs and/or metabolites5
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The Role of PGx in Geriatric ADRs• Frequently hospitalized older adults (≥65 yo) showed significantly higher frequency
of PGx polymorphisms compared to matched older adults with polypharmacy rarely admitted to hospital1• ≥3 hospital admissions in last 2 years and taking ≥5 medications• Limitation: 6 cases and 6 controls (nested case-control)
• CYP450 substrates associated with greater readmission rates and greater healthcare costs2
• At discharge, at least one CYP450 substrate was associated with 10% increase in odds of 90-day readmission (OR of 1.104 in claims and 1.128 in EMR; P<0.001)
• Substrates of CYP450 2D6 and 1A2 reported out individual risk in both cohorts• Any CYP450 substrate associated with increased monthly medical costs (+$397, p<0.003)
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1Finkelstein (2016) Pharmacogenomics Pers Med 9:107‐116.2McCoy (2017) Pharmacogenomics J 17(4):382‐385.
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PGx Clinical Applications GERMLINE & SOMATIC
ONCOLOGY
BRCA / LYNPARZAHER2 / HERCEPTIN
CYP2D6 / TAMOXIFENEGFR / ERBITUXBRAF / ZELBORAF
CYSTIC FIBROSIS
CFTR / KALYDECO
CARDIOLOGY
CYP2C9 / WARFARINVKORC1 / WARFARIN2C19 / CLOPIDOGREL
STATINS
SLCO1B1 / SIMVASTATIN
PSYCHIATRY CYP2D6 / ARIPIPRAZOLE
CYP2C19 / CITALOPRAMCYP2D6 / THIORIDAZINECYP2D6 / VORTIOXETINE
https://www.fda.gov/downloads/drugs/scienceresearch/ucm578588.pdf [FDA Table of Pharmacogenomic Biomarkers in Drug Labeling]https://cpicpgx.org/guidelines/
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Cardiology
•Heart Attack (Myocardial Infarction)• For a major heart attack, two primary treatment
approaches:• Open-heart bypass surgery• Stent placement
• After stent placement• Control blood pressure• Control cholesterol• Prevent additional clots
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Cardiology
•Clopidogrel, prasugrel, or ticagrelor used to prevent additional clots
•Too much drug: bleeding
•Too little drug: clotting
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• CPIC dosing guidelines for clopidogrel and CYP2C191
• FDA label updated (9/2016) to consider alternatives in CYP2C19 PMs
• Not all studies show genotype influences clinical response2
• Decreased CYP2C19 in vivo activity with older age3
• No age dosage adjustment on FDA label
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1Scott (2013) Clin Pharmacol Ther 94(3): 317–323. 2Rodriguez‐Gonzalez (2018) J Clin Pharmacol 58(10):1274‐1283. 3Bebia (2004) Clin Pharmacol Ther 76(6):618‐27.
CPIC dosing guidelines
Cardiology
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Depression• STAR*D found % patients
achieving remission decreases with added medication trials1
• HCPs underestimate patient emotional burden from multiple medication failures2
• Example of geriatric consideration:• Citalopram maximum dose
20mg/daily due to QTc risk• CYP2C19 variation, not dose or
serum level, shown to be associated with QTc prolongation3
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1Rush (2006) Am J Psychiatry 163(11):1905‐17. 2Mago (2018) Ann Gen Psychiatry 17:20. 3Kumar (2014) J Psychopharmacol28(12):1143‐8. 4Bousman (2018) Curr Opin Psychiatry [Epub ahead of print]
Drug‐gene pairs with highest level of evidence in psychiatry4
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Pain
• Clinical CYP2D6-dosing guidelines available for codeine and tramadol1• CPIC and DPWG
• CYP2D6 PMs associated with decreased analgesic response2
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https://www.pharmgkb.org/chemical/PA449088/guidelinehttps://www.pharmgkb.org/chemical/PA451735/guideline1Obeng (2017) Pharmacotherapy 37(9):1105‐1121.2Stamer (2007) Clin Pharmacol Ther 82(1):41‐7.
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Drugs w/Pharmacogenomic Guidelines
• Clinical Pharmacogenetics Implementation Consortium (CPIC)Antidepressants (e.g., TCAs, SSRIs) Anticoagulants (warfarin)
Pain medications (e.g., codeine)23 guideline publications
• Royal Dutch Association for the Advancement of Pharmacy Pharmacogenetics Working Group
52 drugs are mentioned in their guidelines• Food and Drug Administration (FDA)
130 commonly prescribed drugs have dosing guidelines based on PGX• 80% of the population carry at least one gene mutation affecting
drug metabolism
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FDA Dosing Guidelines• July 2015 – a new medication for schizophrenia
and depression was approved• Brexpiprazole (Rexulti)• 7-10% of the population have decreased clearance of
CYP2D6• Adverse drug reactions due to increased drug exposure at
standard doses• Dose adjustment by 50% for
• CYP2D6 poor metabolizers• CYP2D6 inhibitor• CYP2D6 inducers (Ultra metabolizers may metabolize too
quickly to have a therapeutic response)https://www.otsuka‐us.com/media/static/Rexulti‐PI.pdf. Accessed 10/4/16
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Who’s Using this Information?
• Inova Health System is testing all newborns as of 2/16
•UPMC to test all heart cath lab patients (approx 700 in the next year) as of 2/16
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How Much do We Know?
• Medications impacted by pharmacogenetics are used commonly • From the Top 200 most frequently prescribed drugs
• 13 medications list relevant pharmacogenetic information• Up to 25% of patients take a medication where
pharmacogenetics information has been shown to be relevant
• More than 90% of medications are metabolized by just 6 liver enzymes that are assayed with PGX testing
Vaughan KTL, et al. J Med Lib Assoc 2014;102(1):47‐51.Tom Lynch, PharmD, Amy Price, MD, Eastern Virginia Medical School, Norfolk, Virginia Am Fam Physician. 2007 Aug 1;76(3):391‐396.
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Hindorff LA, MacArthur J (European Bioinformatics Institute), Morales J (European Bioinformatics Institute), Junkins HA, Hall PN, Klemm AK, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Available at: www.genome.gov/gwastudies. Accessed 10/3/2016
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How Much Is there Still to Learn?
• Knowledge about pharmacogenetics is lacking• Only 29% of physicians report any education related to
pharmacogenetics (14.7% in medical school, 23.0% in postgraduate training)
• Only 10.3% of physicians felt adequately informed about pharmacogenetic testing
• Only 12.9% of physicians have ordered a pharmacogenetic test in last 6 months
• This is changing . . .
Stanek EJ, et al. Clin Pharmacol Ther 2012;91(3):450‐8.
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What Are We Trying to Do?
• Improve the patient care• Improve population health•Reduce per capita cost of health care
http://www.aha.org/content/15/brief‐3aim.pdf
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Cost• Cost of pharmacogenetic testing ~$300• Cost of drug therapy
• Plavix/clopidogrel 75mg ($9-90 for 30ct Rx) taken once daily• Effient/prasugrel 10mg ($363-406 for 30ct Rx, brand-only) taken once
daily• Brilinta/ticagrelor 90mg ($315-352 for 60ct Rx, brand-only) taken twice
daily• Savings
• Potential $225-300 savings per month by using clopidogrel• How much does a blood clot cost?• How much does excessive bleeding cost?
Goodrx.comMauri L, et al. NEJM 2014;371(23):2155‐66.
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Cost: Long-Term Care• Long-term care residents, over age 45, with 5 or more Rx
medications• 132 patients received testing for 17 genes, data reviewed by a
pharmacist for clinical recommendations• Approximately half of tested were found to have actionable
findings; of those with actionable findings, pharmacist recommendation was for adjustment of 1-3 drugs
• Drug cost savings alone: $621 per patient saved annually (2-3 year average length of stay?)
• Limitation: variability of the pharmacist vs. guidelines?
Saldivar JS, Taylor D, Sugarman EA, et al. Pharmgenomics Pers Med 2016;9(1‐6).
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Example:
• 76 year old male: famotidine, gabapentin, levothyroxine, metoclopramide, mirtazapine, morphine, omeprazole, promethazine, sertraline, tamsulosin
• CYP2C19 *1/*17 (UM) – ultra rapid metabolizer• HTR2A (rs6311 G/G) – increased susceptibility to SSRI-induced
side effects• Discontinue sertraline (SSRI) likely little contribution to
combination antidepressant therapy with mirtazapine• Estimated savings $907 annually
Saldivar JS, Taylor D, Sugarman EA, et al. Pharmgenomics Pers Med 2016;9(1‐6).
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This Is Simple, Let’s Get Started …• Mechanism-based vs. evidence-based approach to treatment• Other drugs affected? Inducers/Inhibitors• Drug-drug-gene interactions?• Multiple genes at once?• More complicated interpretation?• Lacking guidelines?
Hirsh/Rokach B, et al. Pharmacother 2015;2:140‐7.http://www.fda.gov/Safety/MedWatch/SafetyInformation/ucm327922.htmKisor DF, et al. Pharmacogenetics, Kinetics, and Dynamics for Personalized Medicine. JBL 2013.
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What Are the Potential Benefits?
• Improve efficacy of therapy•Reduce/avoid adverse drug reactions•Select the correct starting dose•Reduce total health care costs
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What Are the Potential Challenges?
• Training/Education• Usefulness• When to order• How to obtain the sample• What to do with the results
• Individual patient-level cost• Doesn’t help with every medication
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More Challenges• Epigenetics – gene expression is modified rather than the genetic
code itself• Traumatic life events or early chronic stress can affect susceptibility to
disease• Phenoconversion – looking strictly at genotype doesn’t tell us
everything• Genotype in one test showed 4% expected to be poor metabolizers of
venlafaxine• Blood tests showed that 27% were poor metabolizers
J Clin Psychiatry. 2013 Jun;74(6):614‐21. doi: 10.4088/JCP.12m07807. Epub 2013 Mar 13
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Discrimination Based on Genetics
• The Burlington Northern Santa Fe Railroad• Secret genetic testing of employees• Predisposition to developing carpal tunnel syndrome
• Genetic Information Nondiscrimination Act (GINA)• Prohibits discrimination by health insurers and employers• Does not apply to life, LTC or disability insurance• Does not cover symptomatic patients
Lauren J. Sismondo, GINA, What Could You Do for Me One Day?: The Potential of the Genetic Information Nondiscrimination Act to Protect the American Public, 21 Wash. U. J. L. & Pol’y 459 (2006), http://openscholarship.wustl.edu/law_journal_law_policy/vol21/iss1/18
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Discrimination Based on Genetics
• These tests do not provide disease risk information
• Therefore fewer ethical, legal and social implications with most PGX testing
• With whole-genome sequencing there may be liabilities to physicians and provider institutions
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How Do We Succeed?
• Use a single lab• Work with a PGX trained pharmacist• Use it as one piece of information with other available
data• Have reasonable expectations – a normal metabolizer
isn’t a bad thing; no news can be good news• Use to guide therapy selection• Use evidence based recommendations
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Who Might Be Tested?•Mental health• > 2 Psychoactive medications• Trigger MDS QI profile for symptoms of depression
without treatment• Psychiatric hospitalizations• Side effects• Persistent symptoms or poor response • A recent study indicated 87% of SSRIs have a gene
conflict
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Who Might Be Tested?•Mental health – continued• Only 30-40% achieve remission with 1st drug • About 50% of antidepressant response is due to genetic
polymorphisms• Matching drugs to symptoms may not increase
response• Ex: Sedating antidepressant for a depressed patient with
insomnia• This was no more helpful with depression than a stimulating
medication1. Kemp, et al. 2008 2. Fabbri, et al 2014. e. Simon, et al. 1998
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Who Might Be Tested?
•Pain management• New diagnosis• New medication• Persistent symptoms• Multiple changes in drug therapy• Side effects• Pain medication allergies
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Who Might Be Tested?
•Pain management – continued• 80% of patients experiencing an adverse event
related to opioids have altered CYP2D6 metabolism
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Who Might Be Tested?
•Cardiovascular disease• Clopidogrel (Plavix), Ticagrelor (Brilinta), Prasugrel
(Effient)• European/African ancestry ~30% have a *2• Oceanian ancestry: ~ 60% have a *2• 36% of the population has a CYP2C19 variant causing clopidogrel
to be ineffective• 28% of the population has a CYP2C19 variant that increases risk of
bleeding on clopidogrel
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Who Might Be Tested?
•Cardiovascular disease – continued• Statins
• Branded drugs • Simvastain – dosing recommendations based on phenotype
• Warfarin• Dosing
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Who Might Be Tested?
• Others• Mental status change• Unexplained falls• Increased fatigue• Unexplained weight loss/gain• Non-responders• Need for increased ADL help
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Where Do We Go from Here?• Medicare B patients
• Many Medicare B patients have no copay for PGX testing• Aetna patients
• Clopidogrel (Plavix)• Tetrabenazine (Xenazine)
• Medicaid patients• Many state Medicaid plans cover PGX testing
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How Do We Get Involved?
•Get order from a prescriber•Test kit• Billing information• Test swabs
•Send to lab•Receive test results
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The Art of Persuasion . . .
• Emphasize the benefits• Less trial and error prescribing• Minimize adverse drug reactions• Improve quality of life• Manage health care costs
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Frequent Questions from Prescribers• I’m not trained to interpret the results
• Work with a group that helps interpret the results • It’s a collaborative process• Set goals for testing
• I don’t want the liability of having the information available• Do you want the liability of not testing?
• There isn’t enough evidence to support it’s use• That may have been true at one time – FDA, CPIC, PharmGKB• Using a lab that recommends evidence-based
recommendations
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Frequent Questions from Family/Residents• How much will it cost?
• This can’t always be predicted. It can vary from nothing to an average of less than $350
• Contact the provider and see if coverage can be determined• How much is preventing a heart attack worth?• How much is effectively treating behaviors or depression worth?
• I don’t want my DNA tested/Social concerns about information genetically linked diseases• This information is kept completely private/HIPAA• The tests look at drug metabolism – pharmacogenetics not genetic tests
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Clinical Example
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Questions?
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Rob Leffler, R.Ph.Vice President of Clinical Servicesp: 502.266.2528e: [email protected]
Thank you!
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