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Deals with the influence of genetic variation on drug response by co-relating gene expression or polymorphism with a drug’s efficacy or toxicity

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  • Much research is underway to understand how genomic information can be used to develop more personalized and cost-effective strategies for using drugs to improve human healthsome patients with depression respond to the first drug they are given, many do not, and doctors have to try another drug. Because each drug takes weeks to take its full effect, patients' depression may grow worse during the time spent searching for a drug that helps
  • Is branch of pharmacology deals with thinflluence of genetic variation i.e gene polymophism either due to incersion , deletion SNP, repeated nucleotide , all these causes the change in drug response, that corelating this change with drug efficacy or toxicity, some genetic variation leads to reductiion in efficay of drugs , some poly causes increase in toxilty, Using a genetic information to predict whether the drug will help to make pateint well or ill
  •  single gene pair, the tasters being homozygous or heterozygous for the dominant allele, the non-tasters homozygous for the recessive allele, first known example,  G6PD / NADPH pathway is the only source of reduced glutathione in red blood cells sulfanamides,premaquine, chloquine,
  • PGt is often a study of the variations in a targeted gene, or group of functionally related genes. PGx, on the other hand is a much broader investigation of genetic variations at the level of the genome.
  • Genetic muiation is a type of genetic polymorphism
  • SNP is probably the most common variation. More than 90% of human genes contain at least one SNP, More than 14 million SNPs have been identified in the human genome. More than 60,000 SNPs are located in the coding regions of the genes, Most SNPs seem to have no apparent effect on gene function. Nonetheless, some SNPs do have profound impact on the function of associated genes.
  • N-acetyltransferase NAT1 NAT2, 4-hydroxylation of debrisoquine (guanathedine ) anti hypertensive by CYP2D6 fallow mono genicmultimodel , poor metabolizers (PM) who have inactive CYP2D6, ultrarapidmetabolizers (UM) who have multiple copies of CYP2D6 and very high activities of 2D6, intermediate metabolizers who have reduced activities of CYP2D6, and extensive metabolizers (EM) who have a normal rate of metabolismBroad/poly--many drugs metabolized by CYP3A5 are also substrates of CYP3A4, the clinical effects of the CYP3A5*3 polymorphism may well be obscured by the presence of functional CYP3A4, or vice versa.
  • 1950s , population variability, intrapetient variability, human genome sequence, recent progress genetic polymorphism of targets……… Pharmacogenetics involves the study of single gene mutations and their effect on drug response. The term pharmacogenomics is much broader and it involves surveying the entire genome to assess several determinants of drug responses,
  • , Warfarin consists of a racemic mixture of two active enantiomers—R- and S- forms
  • Patients with hypertension and albuminuria with insulin-dependent diabetes mellitus were particularly susceptible to ACE inhibition treatment if they carried thehomozygous I/I genotype. the deletion polymorphism of ACE, particularly D/D homozy-gote, is a risk factor for an accelerated loss of kidneyfunction that reduces the long-term beneficial effect ofACE inhibition on progression of diabetic and nondiabetic kidney diseasesIn patients with essential hypertension and left ventricular hypertrophy who participated in a long-term ACE inhibitor therapy, the magnitudes of regression of septal wall thickness and left ventricular mass index during the therapy were less in the D/D group than in the I/I group
  • CYP2D6, CYP2C9, CYP2C19 are highly polymorphic, accounts for 40% of drugs metabolism,
  • Evaluation of human CYP2D locus on 22, inactivation of CYP2D7, CYP2D8 & partial inactivation of CYP2D6…..
  • CYP2D6*4/*4 genotype (PM) had shorter relapse- free time and worse disease-free survival compared with patients with either one or no *4 alleles, On the other hand, higher incidence of moderate or severe hot flashes were found in patients with one or no *4 alleles (20%) compared with homozygotes of the *4 allele (0%). On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifento include information about this gene in the package insert, 7-10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their unique genetic make-up
  • Ondensetron ineffective.. study demonstrated that in users of TCA the risk ofswitching to any other antidepressant within 45 days issignificantly higher in PMs than in EMs. But not seen in with SSRI,
  • South indian 14% PM, 11% north,
  • In the case of acenocoumarol there is increasing clinical evidence that the CYP2C9*3 allele only is related to a low- dose requirement for this drug, a higher frequency of over- anticoagulation and
  • The test analyzes the DNA of a patient to determine the genotype, and prediction of the phenotype can then be made. PCR amplication of the gene.Fragmentation and labeling of the PCR productHybridization and staining on the AmpliChip DNA microarray.Scanning the chip.Data analysis.
  • 6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism. This alters the synthesis and function of RNA and DNA,  6-thioguanine utilises the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) to be converted to 6-thioguanine monophosphate (TGMP)
  • Drug transporters modulate the absorption, distribution, and elimination of drugs by controlling the influx and efflux of drugs in cells. This pg acts as efflux of xenotics ,, cancer chemotheraphy , cross resistance of tumor to many cytotoxic drugs, even though these cell not exposed to earlier.
  • the C421A variant was significantly associated with greater reduction in LDL cholesterol levels in a gene- dose-dependent manner./reducing the biliaryexcretion of diflomotecan and rosuvastatin, causing variations in drug effects
  • OATPs are a large family of membrane transporter proteins for the transport of organic anions, including drugs and metabolites, across the cell membraneOATP1B1 encoded by SLCO1B1 is critical for hepatic uptake of simvastatinacid, the active metabolite of simvastatin
  • OATP1B1 encoded by SLCO1B1 is an influx transporter on the basolateral membrane of hepatocytes
  • 80-fold higher risk of flucloxacillin DILI was attributed to a SNP in the major histocompatibility com- plex (MHC), rs2395029is a selective cyclooxygenase-2 inhibitor efficacious in the symptomatic treatment of osteoarthri- tis and acute painFlucloxacillin is widely used for the treatment of staphylococcal infection but is associated with a characteristic cholestatic hepatitis
  • n trimethoprim-sulfamethoxazole (Sesti
  • Irinotecan is a potent DNA topoisomerase I inhibitorused for the treatment of colorectal and lung cancers. Irinotecan is converted to its active metabolite, SN-38, by carboxylesterase in the liver. However, high levels of SN-38 lead to severe side effects, including severe myelosuppression in 15 to 20% and severe delayed-type diarrhea in 20 to 25%Patients ho- mozygous or heterozygous for the UGT1A1*28 allele have elevated levels of SN-38 and consequently are susceptible to bone marrow and gastrointestinal side effects of SN-38 if treated with a normal dose of irinotecan for cancer therap
  • s a nucleoside analog reverse transcriptase inhibitor (NRTI) ,
  • decision regarding continuation of the trial can be made, Also, this information can help in selecting appropriate patients with normal metabolizingenzymes in phase I clinical trial;it can also help prevent adverse events.Polymorphisms of P2Y 12 receptors in platelets have been identified to be associated withincreased risk of coronary artery disease by haplotype analysis. In the future, this can be a potentialtarget for a drug compound produced against coronary artery disease.
  • The efficacy of a drug, to a great extent, is determined by appropriate target selection, which can be guided by pharmacogenomic methods. HER2 Trastuzumab in breastcance in HER2 expression
  • INR=(PTtest/PTn) ISI
  • generation of active metabolite from clopidogrel depends on the enzymatic balance be- tweenbioactivation by P450s and bioinactivation by he- patic carboxyl esterase 1 and esterase,  The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin, APIXABAN highly selective inhibitor of factor Xa
  • Patients with this variant express fewer UGT1A1 enzymes in their liver and are not able to clear the drug during chemotherapy as effectively as others, thus resulting in a larger dose.
  • The costs associated with treating a bleeding event average $13,500 and a stroke is $39,000, suggesting that an annual net health care savings of as much as $1 billion per year could be realized by integrating genetic testing in the administration of Warfarin therapy
  • market for certain drugs might be too small to justify costs that are incurred by the pharma- ceutical industry in R&D and regulatory approva, US Orphan Drug Law- 1983 — an‘orphan disease’ is a condition that affects fewer than200,000 people in the United States,
  • Pharmacogenomics

    1. 1. Pharmacogenomics Dr Manukumar
    2. 2. • 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
    3. 3. Introduction• Pharmacogenomics:-Deals with the influence of genetic variation on drug response by co- relating gene expression or polymorphism with a drug’s efficacy or toxicity
    4. 4. History1930s, Inability to taste phenylthiocarbamide and an autosomal recessive trait1950s , A deficiency in plasma cholinesterase activity an inherited abnormality of succinylcholine metabolism.Drug induced haemolysis, Glucose-6-phosphate dehydrogenase deficiency.(Africans)
    5. 5. • Pharmacogenetics- is often a study of the variations in a targeted gene, or group of functionally related genes.• Pharmacogenomics , on the other hand is a much broader investigation of genetic variations at the level of the genome Pharmacogenomics includes Pharmacogenetics
    6. 6. Genetic polymorphism / mutation• A difference in DNA sequence among individuals, groups, or populations. Sources include SNPs, sequence repeats, insertions, deletions and recombination.• Changes in DNA sequence which have been conformed to be caused by external agents are also generally called "mutations" rather than "polymorphisms."
    7. 7. Single Nucleotide Polymorphism (SNP)• DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered. …CTAGATACGAACTGCATC… …CTAGATACGGACTGCATC…• More than 14 million SNPs have been identified in the human genome. >60,000 SNPs are located in the coding regions of the genes
    8. 8. CONSEQUENCES OF POLYMORPHISMS• May result in a different amino acid or stop codon• May result in a change in protein function or quantity• No consequence
    9. 9. Human genetics• Monogenic inheritance  Bimodal  Multimodal  Broad• Polygenic inheritance
    11. 11. Genetic polymorphism in drug targets• Warfarin- Vit K epoxide reductase -VKORC1 -- A41S, R58G, V66M, L128R and V45A• ADRB2 gene- Beta receptors – Arg16/Arg16
    12. 12. ACE gene• Angiotensin 1 –converting enzyme , incertion(I)/deletion(D) polymorphism I/I homozygous -> susceptability to ACEI Rx D/D homozygous -> reduce the long-term benificial effect of ACEI, risk of accelerated loss of kidney function
    13. 13. Genetic polymorphism of drug metabolizing enzymes• Enzymes involved in drug metabolism
    14. 14. CYP2D6*• Metabolism of approximately 20-25% of marketing drugs. Beta-blockers, antidepressants, antiarrhythmic, antipsychotics The Pharmacogenomics Journal (2005) 5, 6–13
    15. 15. • Tomoxifen -> ER+ breast cancer CYP2D6*4 --- Poor metabolizer(7-10%)- frequent relapse , worse disease free survival
    16. 16. Selective substrates of CYP2D6
    17. 17. • Antidepressant• in PM- users of TCA the risk of switching to any other antidepressant within 45 days,• UM- therapeutical failure
    18. 18. CYP2C19• CYP2C19*2, CYP2C19*3-- poor metabolizer Pharmacogenomics (2007) 8(9), 1199–1210
    19. 19. CYP2C19 • Diazepam / omeprazole/ Phenytoin 14% 11% • Phenytoin / diazepam toxicity (is) more in poor metabolizer, further detailed studies required.Br J Clin Pharmacol 2003; 56(3): 331-3 Clin Pharmacol Ther 1998; 63(4): 422-7.
    20. 20. CYP2C9
    21. 21. 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
    22. 22. Amplichip CYP450• Determine the genotype of the patient in terms of two CYPP450 enzymes: 2D6 and 2C19• FDA approved the test on December 24, 2004. The AmpliChip CYP450 test is the first FDA approved pharmacogenetic test.
    23. 23. CYP3A4/ CYP3A5• Responsible for the metabolism of more than 50% of clinical drugs• More than 20 CYP3A4 variants have been identified• Virtually all CYP3A4 substrates, with a few exceptions, are also metabolized by CYP3A5.
    24. 24. Other-drug metabolizing enzymes• Thiopurine methyltransferase catalyzes the S- methylation of 6-mercaptopurine, azathioprine, and thioguanine, to inactivate the thiopurine drugs• Patients exhibiting myelosuppression or bone marrow toxicity should be tested for (TPMT) enzyme deficiency. Continue withlower dose.• Atypical butyrylcholinesterase• N-Acetyltransferases slow Acetylators fast Acetylators
    25. 25. Genetic polymorphism of drugs transporters• MDR1 and other ABC transporters play an important role in absorption, distribution, and elimination of many drugs and xenobiotics.• PGP (ABCB1) serves as barrier against entry of compounds into the body, as well as from entering tissues.• Cancer chemotheray – tumor cell over expressed with Pg- drug resistance
    26. 26. • The breast cancer resistance protein (BCRP) is an ABCG2 transporter.• ABCG2 C421A polymorphism influences the pk and therapeutic effect of Rosuvastatin.• Reduced biliary exretion, Greater reduction in LDL cholesterol level in a gene-dose- dependent manner.
    27. 27. • SLC21A6 gene encodes OATP-C, a liver-specific transporter important for hepatic uptake of a variety of endogenous and therapeutic compounds.
    28. 28. Genetic Variables Affecting Adverse Drug Reactions• Drug toxicity can result from the inhibition or activation of a therapeutic target by a drug.• On-target toxicity -> excessive bleeding from high doses of warfarin.• Off-target toxicity -> statin induced myopathy.
    29. 29. Drug induced liver injury• Most common cause of clinical trial termination of new drugs (33%) and a main cause of the withdrawal of clinical drugs from the market.• 80-fold higher risk of flucloxacillin DILI -SNP in the major histocompatibility complex (MHC), rs2395029, HLA-B*5701.• Several SNPs from the MHC class II region that showed strong association with lumiracoxib hepatotoxicity.
    30. 30. • KCNE2 encodes MinK-related peptide 1, a subunit of the cardiac potassium channel.• KCNE2 polymorphisms are associated with inherited long QT syndromes (LQTS) and some drug-induced LQTS
    31. 31. Drug hypersensitivity Drugs The hypersensitivity was strongly Abacavir associated with the HLA polymorphism HLA-B*5701 CBZ-induced hypersensitivity reactionsCarbamazepine were also associated with a TNF promoter polymorphism 308TNF polymorphisms in 5q33 representAsparaginase inherited variation in the risk of asparaginase allergy, and drug allergy and asthma
    33. 33. Potential of Pharmacogenomics
    34. 34. • In todays world, only 30-60% of drugs work effectively to rid a patients illness.• However, with the application of pharmacogenomics, the success rate of drugs will increase to 100% (responders)
    36. 36. Applying PGs Discovery Development • . DISEASE TARGET SELECTING PHARMACO- GENETICS VARIABILITY RESPONDERS GENETICS Choosing Better Improving Predicting the Best Understandin Early Efficacy Targets g of our Decision and Safety. Targets Making
    37. 37. Drug target• identification of a potential target at which the drug can act.• Drugs which are based on targets showing wide polymorphisms can have variations in their effect. Can be avoided,• Polymorphisms of P2Y 12 receptors in platelets increased risk of coronary artery disease - potential target
    38. 38. • Certain research subjects with particular genotypes is used as inclusion/ exclusion criteria.• Prediction of safety of drug- avoiding PM• Prediction of efficacy of drug- selecting a patients with HER2 expression
    39. 39. Cont… PGs in drug developmentImatinib inhibit BCR-ABL tyrosine kinase Mutations T315I and F359V directly affect the contact between Imatinib and the ABL kinase domain-> drug resistance Nilotinib, Nasatinib
    40. 40. FDA issued a black box notice clopidogrel
    41. 41. Drugs Mechanism of action IndicationsTrastuzumab , 1998 HER2/neu receptors Breast CA with HER2 over expressionImatinib , 2001 BCSR-ABL tyrosine kinase CML, GISTGefitinib, 2003 EGFR tyrosine kinase Locally advance NSCLC, domine with EGFR expressionIrinotecan Topoisomerase 1 inhibitor Colon CA, In 2005, the FDA changed the labeling to add recommendations that patients with polymorphisms in UGT1A1 gene, particularly the TA7/*28 variant, should receive lower doses
    42. 42. Barriers1. Complexity of finding gene variations that affect drug response.Millions of SNPs must be identified and analyzed to determine their involvement (if any) in drug response.Many genes are likely to influence responsesLimited knowledge of which genes are involved with each drug response
    43. 43. 2. Disincentives for drug companies to make multiple pharmacogenomic productsMost pharmaceutical companies have been successful with their "one size fits all" approach to drug developmentFor small market- Pharmaceutical companies has to spend hundreds of millions of dollars on pharmacogenomics based drug development!----- “US Orphan Drug law”
    44. 44. Educating healthcare providers & patients• Introducing multiple pharmacogenomic products to treat the same condition for different population subsets• Complicates the process of prescribing and dispensing drugs• Physicians must execute an extra diagnostic step to determine which drug is best suited to each patient• Need for a better understanding of genetics by all physicians
    45. 45. Thank you