PHARMACOGENOMICS

Sanju k Department of pharmacology

KMCH college of pharmacy.

• Pharmacogenomics is the study that examines how genetic variations affect the ways in which people respond to drugs.

• Pharmacogenomics examine many genomic loci including large biological pathways to determine the variability.

• Pharmacogenetics focuses on large clinical effects of single gene variant in small number of patients.

Merits and demerits

MERITS• Improve drug safety, and reduce ADRs;• Tailor treatments to meet patients' unique

genetic pre-disposition, identifying optimal dosing;

• Improve drug discovery targeted to human disease; and

• Improve proof of principle for efficacy trials.

Demerits

• PolymorphismNatural variations in a gene ,DNA sequence or chromosome that have no adverse effects on the individual.

• Allele• An allele is one of a pair of genes that appear at a

particular location on a particular chromosome and control the same characteristic.

PHARMACOGENOMICS IN DRUG DISCOVERY AND DEVELOPMENT

• Through examination of individual response profiles and elucidation of different effect of different compounds on gene expression will lead to target identification,drug discovery and compound selection.

Identification of novel proteins involved in disease processes

Targetting of proteins with variant structure resulting from genetic polymorphism.

Refinement of existing targets to improve specificity of drug action.

Approaches to drug discovery and development

• Development of new drugs to overcome drug resistance or target new drug targets.

• Optimisation of drug metabolism and pharmacokinetics(DMPK) to minimise variations in drug levels

Overcoming drug resistance

• Imatinib >>nilotinib>>nasatinibDrug Target Mutation sites Effect

Imatinib BCR-ABL tyrosine kinase,mast/stem cell growth factor receptor(SCFR,CD117),PDGFR

T315I,F359V(contact regions of drug with ABL domain),P-loop of ATP binding pocket of kinase domain(suitable conformation for binding)

25% of patients with gastrointestinal stromal tumors suffered relapse.

Optimisation of DMPK

• DMPK optimisatisation is a practical and effective approach in developing especially orally active drugs that have predcatable pharmacokinetic profiles and can be administered with reduced need for monitoring and dose adjustment in drug therapy.

Eg:oral anticoagulants• Warfarin>> clopidogrel>>prasugrel>>apixaban

Drug Target Variation causing factor

Drug intermediates

Effect

warfarin VKORC1 CYP2C9 hypersensitation or true resistance

CLOPIDOGREL Antiplatelet and factor Xa

CYP influenced Hepatic carboxyl esterases deactivates active thiol intermediate

(CYP2C19(2oxo),CYP3A4( active thiol))

Lesser degrees of platelet inhibition and increased risk of cardiovascular events in esterase over expressed population

PRASUGREL Antiplatelet and factor Xa

Esterase(less variant)

CYP3A4 Greater platelet aggregation with lesser variability

Pharmacogenetics in practice

• In a large population a medication that is proven efficacious in many patients often fails to work in some other patients.

• Major genetic factors affecting individual drug response include

Therapeutic targets Drug metabolising enzymeDrug transportersTargets of ADR

Therapeutic targetEg1: warfarin

C1173T polymorphism in intron 1 of VKORC1 result in dose change from 15mg/day

to 16mg/day

Eg2.Anti HIV drugs:vicriviroc,maraviroc

Target associated Variants Effects

CCR2,a chemokine receptor for monocyte chemo attractant protein1.

Polymorphism at codon 64 (V64I) with Ile allele

HIV progress to AIDS2 four years later than those carrying wild type allele

CCR5,a chemokine receptor used by HIV as a coreceptor to enter into the target cell

White persons have 32 base pair deletion but it is not find in Africans

Deletions make receptor nonfunctional and less HIV transmission

Eg3 β agonist and ADRB2

Drug Gene mutation Effects

Albuterol 2 SNPs of ADRB2 results in mutations R16G Q27E

Evokes a larger and more rapid broncho dilation response in arg16/arg16 than in carriers of gly16 allele (arg16/gly16,gly16/gly16)

Drug metabolisms

• Cytochrome P450 catalyses the mono oxygenation of lipophilic drugs to give rise to metabolites with altered activity and increased water solubility

• Variable expression of genes encoding these enzyme make effect on drug response depending upon the affinity of the receptors of the metabolite and orginal drug molecule.

Drug Enzyme involved Effect

codeine Decreased expression of CYP2D6

Less metabolism of the drug causes drug to remain in circulation for a longer time causing respiratory side effects

warfarin Reduced CYP2C9 activity in *2 and *3 variants

15% variability in dose requirement

tacrolimus CYP3A5*1 variant Require larger dose to reach targetted Co

CYP2D6 is the rate limiting enzyme in catalysing the conversion of the prodrug tamoxifen into active metabolites 4-hydroxytamoxifen and endoxifen which have significantly higher affinity for the drug target,estrogen receptor.

DRUG TRANSPORTERS

• Drug transporters modulate the absorption,distribution and elimination of drugs by controlling the influx and efflux of drugs

• Increasing evidence indicates genetic polymorphism of transporters can have profound impact on drug diposition,drug efficacy and drug safety.

Drug Transporter Effectdigoxin C3435T

polymorphism of ABCB1 gene encoding p-gp

Reduced serum digoxin concentration

diflometacan ABCG2 heterozygous genotype C421A

300% higher plasma levels

Estrone sulfate, estradiol 17β-D-Glucoronide

OATP-c*9 and *5(gene SLC21A6)

Reduced uptake

ABCC*2 haplotypes causes less exposure to intestinal cell by reducing hepatibiliary secretion and thus reduce incidence of diarrhoea

TARGETS OF ADR

• Idiosyncratic drug reactions characterised by their rare occurance and requirement of multiple exposure are most extreme of individual variability in drug safety.

1. On target drug toxicity:inhibition or activation of a therapeutic target eg:excessive bleeding from high doses of warfarin

2. Off target drug toxicity: interaction between a drug and a target protein differbt from the therapeutic target.eg:statin induced myopathy.

drug gene effectflucloxacillin HLA-B*1 attributed

to SNP in MHCCholestatic hepatitis(drug induced liver injury)

simvastatin Various(about 3lakh) at various loci SNP associated with SLCO1B1

myopathy

Various cardiac and non cardiac drugs

KCNE2 encoding a subunit of cardiac potassium channel

Long QT syndrome (arrhythmia –torsades de pointes)

DRUG HYPERSENSITIVITY

• They are adverse effect OF DRUGS THAT OCCUrs at a dose tolerated by typical subjects and clinically resembles allergy.

• Eg:abacavir hypersensitivity associated with HLA-B*5701(effective antigen presenting molecule) polymorphism.

Thank you