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

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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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