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Demystifying Pharmacogenetics:its evolution and challenges
June 15, 2016
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Many drugs do not work for the conditions they have been prescribed for
Percentage of patients for whom drugs are ineffective
FDA Report “Paving the Way for Personalized Medicine” October 2013 http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/PersonalizedMedicine/UCM372421.pdf (Data taken from chart on page 12 - source of data: Spear, B.B., Heath-Chiozzi, M., & Huff, J. (2001). Clinical application of pharmacogenetics. TRENDS in Molecular Medicine, 7(5), 201-204.)
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2.2Msevere adverse drug events per year
Drugs are dangerous
0
100,000
200,000
300,000
400,000
500,000
600,000
700,000
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Can
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Gurwitz JH. Et al. Incidence and preventability of adverse drug events among older persons in the ambulatory setting. JAMA 2003;189(9):1107-16
FOURTHleading cause of death in the U.S.
100,000deaths per year by properly prescribed drugs
80,000deaths per year by improperly prescribed drugs
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In Canada we spend more on drugs than on doctors
Drugs are expensive
$30Bspent on prescription drugsHospitals
29%
Drugs16%
Physicians14%
16%of total health care spend
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The difference between an ineffective, safe or dangerous drug lies in the plasma concentration of the drug
Drug Metabolism 101 – The Therapeutic Window
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Drugs are activated and/or deactivated by enzymes in the liver in a process called metabolismAny factor that increases of decreases the function of these metabolic enzymes will affect the concentration of a drug within the therapeutic window and therefore alter its efficacy and safety
Phase I MetabolismCytochrome P450 (CYP) enzymes:Activate a pro-drug to active drugConvert an active drug to an active or toxic metaboliteConvert an unexcretable drug to an excretable form Inactivate a drugHumans have 57 genes divided into 18 families and 43 sub-families of CYP
Phase II MetabolismIn order to be cleared from the body some drugs require additional stepsMethylationSulphationAcetylationGlucurionadationGlutathione conjugationGlycine conjugationPerformed by a multitude of different enzymes
Drug Metabolism 101 – Metabolic Enzymes
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Drug metabolizing enzymes are proteins made by liver cells
The instructions for making proteins are encoded in genes
Humans have over 20,000 genes stored on 23 chromosomes, with a complete set located in the nucleus of every cell
Hundreds of genes are related to drug metabolism
Chromosomes and genes are made of DNA, the famous double helix structure consisting of two strands with alternating base pairs
There are over 6B base pairs 99.9% of these are identical in all humans 0.1% difference = 6M variations
Pharmacogenetics is the study of how inter-individual differences in genes result in differences in drug metabolism, specifically
predicting the efficacy and/or toxicity of a drug.
Drug Metabolism 101 –Genetics of Drug Metabolizing Enzymes
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The challenge for physicians is every individual is profoundly different in how they handle medications
Age, gender, weight, kidney function, liver function all matter
•Without understanding the individual and cumulative effects of multiple drugs on an individual’s unique genetics, a physician
cannot accurately predict how a medication will behave
Drug Metabolism 101
Genetics matter:
>90% of the population have at least 1 genetic variant in the enzymes responsible for drug metabolism
Only 7% have all normal variants of the 5 major CYPs
For a given drug, genetic variations result in patients being classified as Poor metabolizers Normal metabolizers or Ultra metabolizers
Complicating this, multiple drugs will have antagonistic or synergistic effects on the same metabolic pathway
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Drug-Druginteractions(DDI)
Drug-Geneinteractions(DG)
Multi-Drug-Gene interactions(DDG)
Up to 42% of ADE’s will still be missedwithout a pharmacogenetic service
Adverse Drug Events (ADE) – Top three causes
Most EMR and PMS systems check for drug interactions 44% Drug-Drug
14% Multi-Drug
19% of ADE’s caused byDrug-Gene Interactions
23% of ADE’s caused byDrug-Drug-Gene Interactions
58%
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The promise of Pharmacogenetics is a personalized dose to optimize efficacy and safety
Pharmacogenetics: Right Drug, Right Dose
Without GeneticsAdvertised Dose – One Size Fits All
With GeneticsPersonalized Dose
Responds to normal dose
Responds to lower dose
Responds to higher dose
Responds to alternative medication
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Hospitalizations (p=.0273) ER visits (p=.0002)0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
18.00%
control arm
intervention arm
Major economic impact caused by ER visits, hospitalizations and disability from work
Pharmacogenetics can reduce hospitalizations and ER visits
Patients > 65 years on 3 or more medicationsSource: AMCP 2015 Meeting Abstract U36
39%reduction
71%reduction
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1. Standard of care
2. The economics of preventable adverse drug events
3. Digital health platforms
Interplay of 3 Forces affecting Pharmacogenetics
How will Pharmacogenetics benefit the insurance industry?
Right drug, right person, the first time
Prior authorization
Improved health outcomes
Reduced drug spend
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1.The use of pharmacogenetics is becoming a standard of care for the prescription of some drugs.
2.The widespread use of pharmacogenetics will likely reduce health care and disability costs – but this needs to be proven to be cost effective
3.Widespread use of pharmacogenetics in primary care will depend on an effective pan-Canadian digital health platform that brings simple, actionable recommendations to health care providers at the point of care.
Conclusion
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