pharmacogentics_ dr . rehan.pptx

7/29/2019 Pharmacogentics_ Dr . Rehan.pptx

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Pharmacogenetics

and its importance in drugdevelopment


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Genetic diversity contributes to

both disease susceptibility and

variability in response to drug

therapy. Human genome: variation

between individuals.


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Monogenic: due to allelic variation at a singlegene(Sickle cell, CYP2D6, Cystic fibrosis)

Polygenic: due to variations at two or moregenes(Alzheimers disease)

Polymorphic: frequently occurring monogenic variantsoccurring at a frequency >1%

variations in genome account for individual responsesto drugs. Therefore,

Optimized medicines for individualsReduction in adverse drug reactions

Expedient development of new drugs


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Pharmacogenomics

The science ofhow genes affect the way people respond

to drugs

How genes affect

the way our body processes drugs (pharmacokinetics)

the interaction of drugs with receptors (pharmacodynamics)

the treatment efficacy and adverse side effects

_ particular emphasis on improving drug safety


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Pharmacogenetics

A subset of pharmacogenomics

The study of how inherited variationaffects drugresponse and metabolism

Enables physicians to know which medications will besafe and effective for which patients, based on theirgenotype

Ideal situation is when Candidate genesassociated with response and side effects/toxicityare known


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Pharmacogenetic approaches

Makes researchers enable to:

Identify genes involved in disease

Understand how genes and the proteins they

produce are affected by various drug

candidates

Effectively choose target populations to be

used in clinical trials


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Why is this a good approach?

Drugs can be dangerous

Many people have severe adverse reactions to drugs

Many people respond to drugs at different doses

Many drug treatments are horribly unpleasant, painful

Drugs are expensive (to take and to make)

Ineffective drugs are a waste of money to take

Drug development needs to account for response

variability

Genetics provide a prioriinformation

Genetics dont change (except in cancer)

Genetics can point to the cause not just the symptom


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History

1959 - Freidrich Vogel coined the termpharmacogenetics after discovering polymorphicenzymes

Fast increase in awareness of the interaction of drugand drug response

First observation of genetic variation in drug responsein 1950s

- muscle relaxant metabolised by N-acetyltransferase(NAT)- variant of enzyme_less efficient

- slow and fast acetylers


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Cytochrome P450 oxidases

(CYPs)__in drug metabolism Part of innate system for

clearing the body ofxenobiotics

Genetic variations in CYP

family isoenzymes (CYP2D6,CYP2C9 etc) affect largepopulations

Highly polymorphic (58 inCYPs)

Variants encode for non-functional enzymes, poormetabolisers, and ultrarapid metabolisers

CYP2D61975 Smith and colleagues ingest a

drug they are testing

He had a bad reaction but hiscolleagues did not

Family studies revealed geneticinheritance

Enzyme discovered andcharacterized

Enzyme cDNA sequenced andvariants found (1990)

gene important for many drugs (ismonogenic)

Over 75 known allelic variations


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A brief aside into modern genetics


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SNPs

Most common and well studied

form of variation

Gene mutations are rare, 1% population frequency

SNPs exists about every 1000

bases, ie. ~3,000,000/genome


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SNPs and Pharmacogenetics

. G G T A A C T G

. G G C A A C T G ...

use of SNPs to measure drug Responses_ SNP linkage

disequilibrium profiles

SNP can be identified by Genome sequencing of individuals


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Patients with efficacy

in clinical trials

Patients without efficacy

in clinical trials

Predictive ofefficacy

Predictive of no efficacy


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Thiopurines and TPMT Thiopurine methyl transferase(TPMT) metabolises thiopurine drugs(e.g.,

mercaptopurine, azathiopurine etc.)

TPMT activity is polymorphic(3 allels)

If Variation in TPMT_other pathway__metabolite toxic in high conc.(bonemarrow suppression)

By determining TPMT activity in patients before they receive thiopurines,enzyme efficacy can be determined

ethnic differences in TPMT activity

N

NNH

N

SH

N

NNH

N

SCH3

TPMT

SAM SAH

6-mercaptopurine 6-methylmercaptopurine


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The Technology: Genotyping Uses a microarray to measure a limited

predefined set of SNPs Very fast

Excellent coverage ofcommon variation(SNP)

Relies on Linkage Disequilibirum

Genome scans with genotyping chips that areused in GWAS studies and provide customerswith a write-up of individual risk for varioustraits and diseases and testing for 500,000known SNPs. Costs range from $995 to $2500

A T C G A A A T G C A T G A C C T T T G A T A T G A T C G G C T G C A G T C A G C

T T C G A A G T G C A T G A C T T T T G A C A T G A G C G G C G G C C C A C A G C

Microarray

Common Variation Rare Variation No Recorded Variation


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Sequencer

A T C G A A A T G C A T G A C C T T T G A T A T G A T C G G C T G C A G T C A G C

T T C G A A G T G C A T G A C T T T T G A C A T G A G C G G C G G C C C A C A G C

Common Variation Rare Variation No Recorded Variation

The Technology: DNA Sequencing Captures everybase pair in the

genome (3,000,000,000) (Currently) low throughput (slow)

Captures common, rare, andpersonal variation

A disposable DNA sequencingdevice _under $900

portable and easy to use


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Utility of pharmacogenetics

Determining appropriate dosing Avoiding unnecessary toxic treatments

Ensuring maximal efficacy

Reducing adverse side effects

Developing or choosing novel treatments

Can also explain variable response to illicit drugs


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Warfarin: dosage Most widely used anticoagulant in

the world A blood thinner

Prescribed doses vary widely(1-40mg/ day)

Therapuetic index is very low High risk of bleeding early in

treatment

Two genes involved in warfarinmetabolism: CYP2C9 and

VKORC1(vitamin K oxidereductase)

Warfarin is metabolized by CYP2C9, andexerts its anticoagulant effect byinhibiting the (VKORC1).


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CYP2C9 (3 defective alleles with 2 & 3 causing

reduced activity)

person has normal*1/*1one polymorphism *1/*2

both polymorphisms *2/*3

CYP2C9 genotype Time to stable dose

*1/*1 extensive(normal) metabolizer 4 - 5 days

*1/*2 intermediate metabolizer 8 -10 days

*1/*3, *2/*2, *3/*3 intermediate or poor

metabolizer12-15 days


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In the VKORC1 SNP

G allele is replaced by the A allele

people with A allele (or "A haplotype") produceless VKORC1.

Thus lower warfarin doses are needed to inhibitVKORC1 in this case (i.e., to produce ananticoagulant effect in carriers ofA allele.

It means Dose can be predicted based on geneticvariations identified by DNA tests.


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Homozygous wild-type CYP2C9 and VKORC1

Carrier ofCYP2C9 mutant allele

Carrier ofVKORC1 mutant allele

l ff


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Plavix: effectiveness Anti-clotting drug

Prescribed for coronary artery disease

and those who have suffered a heart

attack or stroke or have a stent

A pro-drug

Acts when Converted to activeform(active metabolite) in the liver by

CYP2C19

Poor metabolizers treated with Plavixshow more cardiovascular events

than those with normal CYP2C19

function.


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CYP2C19 mutant carriers had reduced presence

of the active ingredient (pharmacokinetics) and

reduced thinning (pharmacodynamics)

Alleles of CYP2C19 making up patients genotype

Allele 1__fully functional metabolism

Allele2,3__no functional metabolismAllele 4,5,6,7,8 and others__reduced(or no)

functional metabolism

2 loss of functional alleles= Poor metabolizers

(thus alternative treatment)


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Hepatitis C

Peg-Interferon -2a

Interferons are proteins

made in response to virus

Treatment for Hepatitis C

Virus alonwith Ribavirin

Highly toxic treatment

Highly variable response,

in different ethnic

populations

Very expensive


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One mutation near IL28B gene (encoding interferon lambda 3)

increased efficacy of treatment two-fold This mutation is different in and explains half of the ethnic

variability in treatment in different ethnicities

Treatment response can be predicted


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Personalized Medicine

There is an emerging goal among translational

scientists to make medical practice morepersonalized

Pharmacogenetics is an important step towardsthat goal


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Pharmacogenetics_ Advantages

The genotype of an individual is essentially invariable and remainsunaffected by the treatment itself.

Pharmacogenetics is a very useful and important tool in predictingwhich drugs will be effective in various patients

Molecular biology techniques provide an accurate assessment ofthe genotype of an individual (means more accurate drug).

Increasing amount ofgenomic information available. This provides

the necessary data for comprehensive studies of individual genesand broad investigation ofgenome-wide variation.


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The ease ofaccessibility to genotype information throughperipheral blood or saliva sampling and advances in moleculartechniques has increased the feasibility ofDNA collection andgenotyping in large-scale clinical trials.

The use of personalized medicine if widely adopted, it willmake medical trials more efficient.

The use of personalized medicine will also lower the coststhat come about due to adverse drug side effects andprescription of drugs that have been proven ineffective incertain genotypes

With pharmacogenetics, it is possible to develop and license adrug specifically intended for those who are not geneticallyat risk for adverse side effects.


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Thankyou

pharmacogentics_ dr . rehan.pptx

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