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SIRISHAANNAVARAPU
DEPT OF PHARMACOLOGY, KIMS
Introduction
• Pharmacogenomics deals with the influence of
genetic variation on drug response by co-relating
gene express...
Introduction
• Pharmacogenetics is often a study of the variations
in a targeted gene, or group of functionally related
ge...
Pharmacogenomics Pharmacogenetics Genetic toxicology
use of genetic
information to guide
the choice of drug
and dose on an...
NORMAL GENE SNP VARIANT GENE
TODAY’S DRUG
PHARMACOGENOMIC DRUG
Principle of Pharmacogenomics
Potential of Pharmacogenomics
GENETICS AND MUTATION
Genotype
• The genetic constitution of an individual.
Experimental evaluation of Genotype (Genotyping)
Collect blood (> 1 ...
Genetic polymorphism / mutation
• Mutations are inheritable changes produced in the
genetic information stored in the DNA ...
Single Nucleotide Polymorphism
(SNP)
• DNA sequence variation that occurs when a single
nucleotide in the genome sequence ...
Consequences of polymorphisms
• May result in a different amino acid or stop
codon
• May result in a change in protein fun...
ADVANTAGES AND
DISADVANTAGES OF
PHARMACOGENOMICS
Advantages of pharmacogenomics
Barriers of pharmacogenomics
1. Complexity of finding gene variations that affect drug
response.
 Millions of SNPs must b...
Barriers of pharmacogenomics
2. Educating healthcare providers & patients
• Complicates the process of prescribing and
dis...
Barriers of pharmacogenomics
3. Disincentives for drug companies to make multiple
pharmacogenomic products
 Most pharmace...
Amphichip
• Determine the genotype of the patient in terms of two
CYPP450 enzymes: 2D6 and 2C19
• FDA approved the test on...
PHARMACOGENOMICS IN
DRUG METABOLISM
Role of genes in PK & PD
Candidate genes for variable drug
response
(1) Proteins involved in drug transport:
Drug transporters (e.g. ABC and SLC) s...
Pharmacogenomics of drug
transporters
• PGP (MDR 1) serves as barrier against entry of
compounds into the body, as well as...
OATP-C*5 and OATP-C*9 have
reduced uptake of OATP-C substrates
High plasma levels of pravastatin
Increased toxicity and re...
Enzymes involved in drug
metabolism
Effects of CYP variants on
therapeutic efficacy
Examples of Genetic Polymorphisms
Influencing Drug Response
GENE PRODUCT (GENE) RESPONSES AFFECTED
CYP2C9 Anticoagulant ef...
CYP2D6
CYP 2C
• CYP2C9 * 2 and CYP2C9 * 3 variants are of
significance- PM
Drugs whose safety and efficacy
are affected by gene variations
Using pharmacogenomics to predict
and prevent adverse drug reactions
• Abacavir:
• Patients who carry the HLA-B*5701 allel...
• Irinotican: Patients homozygous or heterozygous for
the UGT1A1*28 allele have elevated levels of SN-38
and consequently ...
Using pharmacogenomics to
predict effectiveness
• Clopidogrel:
• CYP2C19, mediates the conversion of clopidogrel
into the ...
• Tamoxifen:
• ER+ breast cancer
• CYP2D6*4 --- Poor metabolizer(7-10%)- frequent
relapse , worse disease free survival
Using pharmacogenomics to
predict optimal dose
• Warfarin:
• Warfarin has a narrow therapeutic index; variations in
CYP2C9...
Targets and receptors
Angiotensin-converting
enzyme (ACE)
ACE inhibitors (e.g.,
enalapril)
Renoprotective effects,
hypoten...
PHARMACOGENOMICS IN
CLINICAL TRIALS
Applying PGs
.
DISEASE
GENETICS
TARGET
VARIABILITY
SELECTING
RESPONDERS
PHARMACO
GENETICS
Discovery Development
Choosing
t...
Pharmacogenomics in various stages
of drug development
• Drug target identification –identification and
characterization o...
References
• Ellis KJ, Stouffer GA, McLeod HL, Lee CR.
Clopidogrel pharmacogenomics and risk of
inadequate platelet inhibi...
• Mallal S, Phillips E, Carosi G, Molina JM, Workman
C, Tomazic J et al. (2008). HLA-B*5701 screening
for hypersensitivity...
THANK YOU
Pharmacogenomics
Pharmacogenomics
Pharmacogenomics
Pharmacogenomics
Pharmacogenomics
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Pharmacogenomics

  1. 1. SIRISHAANNAVARAPU DEPT OF PHARMACOLOGY, KIMS
  2. 2. 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 • It intends to identify individuals who are either more likely or less likely to respond to a drug, as well as those who require altered dose of certain drugs
  3. 3. Introduction • Pharmacogenetics is often a study of the variations in a targeted gene, or group of functionally related genes. • Pharmacogenomics is the use of genetic information to guide the choice of drug and dose on an individual basis.
  4. 4. Pharmacogenomics Pharmacogenetics Genetic toxicology use of genetic information to guide the choice of drug and dose on an individual basis. The study of genetic basis for variability in drug Response Study of the effect of chemical or physical agents on the heredity material (DNA) and on the genetic process of living cells. Differences
  5. 5. NORMAL GENE SNP VARIANT GENE TODAY’S DRUG PHARMACOGENOMIC DRUG Principle of Pharmacogenomics
  6. 6. Potential of Pharmacogenomics
  7. 7. GENETICS AND MUTATION
  8. 8. Genotype • The genetic constitution of an individual. Experimental evaluation of Genotype (Genotyping) Collect blood (> 1 ml) Isolate DNA from nucleated blood cells. Amplify number of copies of DNA by the Polymerase Chain Reaction (PCR). Genotype by sequencing or probing.
  9. 9. Genetic polymorphism / mutation • Mutations are inheritable changes produced in the genetic information stored in the DNA of living cells. Mutation is a difference in DNA sequence among individuals, groups, or populations. Sources include SNPs, sequence repeats, insertions, deletions and recombination.
  10. 10. Single Nucleotide Polymorphism (SNP) • DNA sequence variation that occurs when a single nucleotide in the genome sequence is altered. …CTAGATACGAACTGCATC… …CTAGATACGGACTGCATC…
  11. 11. Consequences of polymorphisms • May result in a different amino acid or stop codon • May result in a change in protein function or quantity • No effect
  12. 12. ADVANTAGES AND DISADVANTAGES OF PHARMACOGENOMICS
  13. 13. Advantages of pharmacogenomics
  14. 14. Barriers of pharmacogenomics 1. 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  Confidentiality, privacy and the use and storage of genetic information
  15. 15. Barriers of pharmacogenomics 2. Educating healthcare providers & patients • 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
  16. 16. Barriers of pharmacogenomics 3. 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
  17. 17. Amphichip • Determine the genotype of the patient in terms of two CYPP450 enzymes: 2D6 and 2C19 • FDA approved the test on December 24, 2004. The AmphiChip CYP450 test is the first FDA approved pharmacogenetic test.
  18. 18. PHARMACOGENOMICS IN DRUG METABOLISM
  19. 19. Role of genes in PK & PD
  20. 20. Candidate genes for variable drug response (1) Proteins involved in drug transport: Drug transporters (e.g. ABC and SLC) show considerable genetic variation including many functional polymorphisms. (2) Genes that code for drug-metabolizing enzymes (DME): Most DME-encoding genes have polymorphisms that have been shown to influence enzymatic activity.
  21. 21. Pharmacogenomics of drug transporters • PGP (MDR 1) serves as barrier against entry of compounds into the body, as well as from entering tissues
  22. 22. OATP-C*5 and OATP-C*9 have reduced uptake of OATP-C substrates High plasma levels of pravastatin Increased toxicity and reduced efficacy
  23. 23. Enzymes involved in drug metabolism
  24. 24. Effects of CYP variants on therapeutic efficacy
  25. 25. Examples of Genetic Polymorphisms Influencing Drug Response GENE PRODUCT (GENE) RESPONSES AFFECTED CYP2C9 Anticoagulant effect of warfarin CYP2C19 Peptic ulcer response to omeprazole CYP2D6 Tardive dyskinesia from antipsychotics, narcotic side effects, codeine efficacy, imipramine dose requirement, β blocker effect
  26. 26. CYP2D6
  27. 27. CYP 2C • CYP2C9 * 2 and CYP2C9 * 3 variants are of significance- PM
  28. 28. Drugs whose safety and efficacy are affected by gene variations
  29. 29. Using pharmacogenomics to predict and prevent adverse drug reactions • Abacavir: • Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. • Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of a hypersensitivity reaction.
  30. 30. • Irinotican: Patients homozygous or heterozygous for the UGT1A1*28 allele have elevated levels of SN-38 and consequently are susceptible to bone marrow and gastrointestinal side effects
  31. 31. Using pharmacogenomics to predict effectiveness • Clopidogrel: • CYP2C19, mediates the conversion of clopidogrel into the active metabolite. Patients who carry variations in CYP2C19 are considered poor metabolizers and show reduced ability to convert clopidogrel into its active metabolite, resulting in a diminished antiplatelet effect.
  32. 32. • Tamoxifen: • ER+ breast cancer • CYP2D6*4 --- Poor metabolizer(7-10%)- frequent relapse , worse disease free survival
  33. 33. Using pharmacogenomics to predict optimal dose • Warfarin: • Warfarin has a narrow therapeutic index; variations in CYP2C9 and VKORC1, make it difficult to predict the effective dose. Those carrying certain CYP2C9 and VKORC1 variations are likely to require altered doses and may require prolonged time to reach a stable maintenance dose.
  34. 34. Targets and receptors Angiotensin-converting enzyme (ACE) ACE inhibitors (e.g., enalapril) Renoprotective effects, hypotension, left ventricular mass reduction, cough Thymidylate synthase Methotrexate Leukemia response, colorectal cancer response β2 Adrenergic receptor β2 Antagonists (e.g., albuterol, terbutaline) Bronchodilation, Dopamine receptors Antipsychotics Antipsychotic response (D2, D3, D4), tardive dyskinesia
  35. 35. PHARMACOGENOMICS IN CLINICAL TRIALS
  36. 36. Applying PGs . DISEASE GENETICS TARGET VARIABILITY SELECTING RESPONDERS PHARMACO GENETICS Discovery Development Choosing the Best Targets Better Understandin g of our Targets Improving Early Decision Making Predicting Efficacy and Safety
  37. 37. Pharmacogenomics in various stages of drug development • Drug target identification –identification and characterization of gene coding for the drug target and to assess the variability. • Phase I II &III – patient selection, inclusion and exclusion criteria, dose range selection, dose modification ,interpretation of trial result based on Pharmacogenetic test results. • Phase IV analysis of reported adverse effects with pharmacogenetic tests.
  38. 38. References • Ellis KJ, Stouffer GA, McLeod HL, Lee CR. Clopidogrel pharmacogenomics and risk of inadequate platelet inhibition: U.S. FDA recommendations. (2009). Pharmacogenomics 10(11):1799–1817. • Collins FS. 2010. The Future of Personalized Medicine. NIH Medline Plus 5(1):2–3. • Belle DJ, Singh H. (2008). Genetic Factors in Drug Metabolism. Am Fam Physician 77(11):1553–1560. • Rollason V, Samer C, Piguet V, Dayer P, Desmeules J. (2008). Pharmacogenomics of analgesics: Toward the individualization or prescription. Pharmacogenomics 9(7):905–933.
  39. 39. • Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J et al. (2008). HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med 358(6):568–579. • Willmann S, Edginton AN, Coboeken K, Ahr A, Lippert J. (2009). Risk to the Breast-Fed NeonateFrom Codeine Treatment to the Mother: A Quantitative Mechanistic Modeling Study. Clin Pharmacol Ther 86(6):634–643. • Ingelman-Sundberg M, Sim SC, Gomez A,Rodriguez-Antona C. (2007). Influence of cytochrome P450 polymorphisms on drug therapies:Pharmacogeneic, pharmacoepigenetic, and clinical aspects. Clin Pharmacol Ther 116:496–526.
  40. 40. THANK YOU
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