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Pharmacogenomics

Dr Manukumar


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Introduction/history Pharmacogenetics/pharmacogenomics

Genetic polymorphism Genetics polym of drug target Genetic polym of metabolizing enzymes Drug Transporters Drug discovery & development PGs drugs Barrier of PGs


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History

1930s, Inability to taste phenylthiocarbamideand an autosomal recessive trait

1950s , A deficiency in plasma cholinesteraseactivity an inherited abnormality ofsuccinylcholine metabolism.

Drug induced haemolysis, Glucose-6-phosphatedehydrogenase deficiency.(Africans)


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Pharmacogenetics - is often a study of thevariations in a targeted gene, or group offunctionally related genes.

Pharmacogenomics , on the other hand is amuch broader investigation of geneticvariations at the level of the genome

Pharmacogenomics includes Pharmacogenetics


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Genetic polymorphism / mutation

A difference in DNA sequence amongindividuals, groups, or populations. Sourcesinclude SNPs, sequence repeats, insertions,deletions and recombination.

Changes in DNA sequence which have beenconformed to be caused by external agentsare also generally called "mutations" ratherthan "polymorphisms."


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Single Nucleotide Polymorphism(SNP)

DNA sequence variation that occurs when asingle nucleotide in the genome sequence isaltered.

CTAGATACG AACTGCATC CTAGATACGGACTGCATC

More than 14 million SNPs have beenidentified in the human genome. >60,000SNPs are located in the coding regions of the

genes


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CONSEQUENCES OF POLYMORPHISMS

May result in a different amino acid orstop codon

May result in a change in proteinfunction or quantity

No consequence


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Human genetics

Monogenic inheritance Bimodal Multimodal

Broad Polygenic inheritance


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DRUGTARGETS

DRUGMETABOLIZING

ENZYMES

DRUGTRANSPORTERS

PHARMACOKINETICSPHARMACODYNAMICS

Variability inEfficacy/Toxicity


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Genetic polymorphism in drugtargets

Warfarin- Vit K epoxide reductase -VKORC1 --A41S, R58G, V66M, L128R and V45A

ADRB2 gene- Beta receptors Arg16/Arg16


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ACE gene

Angiotensin 1 converting enzyme ,incertion(I)/deletion(D) polymorphism

I/I homozygous -> susceptability to ACEI RxD/D homozygous -> reduce the long-termbenificial effect of ACEI, risk of accelerated loss ofkidney function


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Genetic polymorphism of drugmetabolizing enzymes

Enzymes involved in drug metabolism


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CYP2D6*

Metabolism of approximately 20-25% of marketingdrugs. Beta-blockers, antidepressants,antiarrhythmic, antipsychotics

The Pharmacogenomics Journal (2005) 5, 6 13


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Tomoxifen -> ER+ breast cancerCYP2D6*4 --- Poor metabolizer(7-10%)-frequent relapse , worse disease free survival


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Selective substrates of CYP2D6


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Antidepressant

in PM- users of TCA the risk of switching toany other antidepressant within 45 days, UM- therapeutical failure


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CYP2C19

CYP2C19*2, CYP2C19*3-- poor metabolizer

Pharmacogenomics (2007) 8(9), 1199 1210


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CYP2C9


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CYP2C9

16% of clinical drugs metabolized CYP2C9 * 2 and CYP2C9 * 3 variants are of

significance- PM 80% of the pharmacologically more active S-

enantiomer of warfarin is eliminated. CYP2C9 activity is rate-limiting in Phenytoin

metabolic clearance


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Amplichip CYP450

Determine the genotype of the patient interms of two CYPP450 enzymes: 2D6 and2C19

FDA approved the test on December 24, 2004.The AmpliChip CYP450 test is the first FDAapproved pharmacogenetic test.


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CYP3A4/ CYP3A5

Responsible for the metabolism of more than50% of clinical drugs

More than 20 CYP3A4 variants have beenidentified

Virtually all CYP3A4 substrates, with a fewexceptions, are also metabolized by CYP3A5.


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Genetic polymorphism of drugstransporters

MDR1 and other ABC transporters play animportant role in absorption, distribution, andelimination of many drugs and xenobiotics.

PGP (ABCB1) serves as barrier against entry ofcompounds into the body, as well as fromentering tissues.

Cancer chemotheray tumor cell overexpressed with Pg- drug resistance


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The breast cancer resistance protein (BCRP) isan ABCG2 transporter.

ABCG2 C421A polymorphism influences the pkand therapeutic effect of Rosuvastatin.

Reduced biliary exretion, Greater reduction inLDL cholesterol level in a gene-dose-dependent manner.


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SLC21A6 gene encodes OATP-C, a liver-specifictransporter important for hepatic uptake of avariety of endogenous and therapeuticcompounds.


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Genetic Variables AffectingAdverse Drug Reactions

Drug toxicity can result from the inhibition oractivation of a therapeutic target by a drug.

On-target toxicity -> excessive bleeding fromhigh doses of warfarin .

Off-target toxicity -> statin induced myopathy.


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Drug induced liver injury

Most common cause of clinical trialtermination of new drugs (33%) and a maincause of the withdrawal of clinical drugs fromthe market.

80-fold higher risk of flucloxacillin DILI -SNP inthe major histocompatibility complex (MHC),rs2395029, HLA-B*5701.

Several SNPs from the MHC class II region thatshowed strong association with lumiracoxib hepatotoxicity.


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Drug hypersensitivity

Drugs

AbacavirThe hypersensitivity was stronglyassociated with the HLA polymorphism

HLA-B*5701

CarbamazepineCBZ-induced hypersensitivity reactionswere also associated with a TNFpromoter polymorphism 308TNF

Asparaginase polymorphisms in 5q33 representinherited variation in the risk ofasparaginase allergy, and drug allergy andasthma


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NORMAL GENE SNP VARIANT GENE

TODAYS DRUG

PHARMACOGENOMIC DRUG

Principle of Pharmacogenomics :


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Potential of Pharmacogenomics


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In today's world, only 30-60% of drugs work effectively to rida patient's illness.

However, with the application of pharmacogenomics, thesuccess rate of drugs will increase to 100% (responders)


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APPLICATIONS IN DRUGDEVELOPMENT


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Applying PGs

.

.

DISEASEGENETICS

TARGETVARIABILITY

SELECTINGRESPONDERS

PHARMACO-GENETICS

Discovery Development

Choosingthe BestTargets

BetterUnderstandin

g of our

Targets

ImprovingEarly

Decision

Making

PredictingEfficacy

and Safety


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Drug target

identification of a potential target at whichthe drug can act.

Drugs which are based on targets showingwide polymorphisms can have variations intheir effect. Can be avoided,

Polymorphisms of P2Y 12 receptors inplatelets increased risk of coronary arterydisease - potential target


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Certain research subjects with particulargenotypes is used as inclusion/ exclusioncriteria.

Prediction of safety of drug- avoiding PM Prediction of efficacy of drug- selecting a

patients with HER2 expression


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Cont PGs in drug development

Imatinib inhibit BCR-ABL tyrosine kinase

Mutations T315I and F359V directlyaffect the contact between Imatinib andthe ABL kinase domain -> drug resistance

Nilotinib, Nasatinib


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d bl k b


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FDA issued a black box noticeclopidogrel


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Drugs Mechanism of action Indications

Trastuzumab , 1998 HER2/neu receptors Breast CA with HER2 overexpression

Imatinib , 2001 BCSR-ABL tyrosine kinase CML, GIST

Gefitinib, 2003 EGFR tyrosine kinasedomine

Locally advance NSCLC,with EGFR expression

Irinotecan Topoisomerase 1 inhibitor Colon CA, In 2005, the FDAchanged the labeling toadd recommendations thatpatients with

polymorphisms in UGT1A1gene, particularly theTA7/*28 variant, shouldreceive lower doses


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Barriers

1. Complexity of finding gene variations thataffect drug response .Millions of SNPs must be identified andanalyzed to determine their involvement (ifany) in drug response.Many genes are likely to influence responsesLimited knowledge of which genes areinvolved with each drug response


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2. Disincentives for drug companies to makemultiple pharmacogenomic productsMost pharmaceutical companies have beensuccessful with their "one size fits all"approach to drug developmentFor small market- Pharmaceutical companieshas to spend hundreds of millions of dollarson pharmacogenomics based drugdevelopment!----- US Orphan Drug law


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