Demystifying Pharmacogenetics

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
HeartDisease
Cancer
Stroke
CarCrashes
Rx
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%
Drugs
16%
Physicians
14%
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 metabolism
Any 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 Metabolism
Cytochrome P450 (CYP) enzymes:
Activate a pro-drug to active drug
Convert an active drug to an active or toxic metabolite
Convert an unexcretable drug to an excretable form
Inactivate a drug
Humans have 57 genes divided into 18 families and 43 sub-families of CYP
Phase II Metabolism
In order to be cleared from the body some drugs require additional steps
Methylation
Sulphation
Acetylation
Glucurionadation
Glutathione conjugation
Glycine conjugation
Performed 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-Drug
interactions
(DDI)
Drug-Gene
interactions
(DG)
Multi-Drug-
Gene
interactions
(DDG)
Up to 42% of ADE’s will still be missed
without 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 by
Drug-Gene Interactions
 23% of ADE’s caused by
Drug-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 Genetics
Advertised Dose – One Size Fits All
With Genetics
Personalized Dose
Responds to
normal dose
Responds to
lower dose
Responds to
higher dose
Responds to
alternative
medication

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0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
16.00%
18.00%
Hospitalizations (p=.0273) ER visits (p=.0002)
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 medications
Source: 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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Demystifying Pharmacogenetics

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