pharmacogenomics june24
TRANSCRIPT
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