pharmacogenomics is application of genetics to develop personalized medicine

1. SIRISHAANNAVARAPU
DEPT OF PHARMACOLOGY, KIMS

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. 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. 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. NORMAL GENE SNP VARIANT GENE
TODAY’S DRUG
PHARMACOGENOMIC DRUG
Principle of Pharmacogenomics

6. Potential of Pharmacogenomics

7. GENETICS AND MUTATION

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. 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. Single Nucleotide Polymorphism
(SNP)
• DNA sequence variation that occurs when a single
nucleotide in the genome sequence is altered.
…CTAGATACGAACTGCATC…
…CTAGATACGGACTGCATC…

12. 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

13. ADVANTAGES AND
DISADVANTAGES OF
PHARMACOGENOMICS

14. Advantages of pharmacogenomics

15. 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

16. 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

17. 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

18. 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.

19. PHARMACOGENOMICS IN
DRUG METABOLISM

20. Role of genes in PK & PD

21. 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.

22. Pharmacogenomics of drug
transporters
• PGP (MDR 1) serves as barrier against entry of
compounds into the body, as well as from entering
tissues

23. OATP-C*5 and OATP-C*9 have
reduced uptake of OATP-C substrates
High plasma levels of pravastatin
Increased toxicity and reduced
efficacy

24. Enzymes involved in drug
metabolism

25. Effects of CYP variants on
therapeutic efficacy

26. 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

27. CYP2D6

28. CYP 2C
• CYP2C9 * 2 and CYP2C9 * 3 variants are of
significance- PM

29. Drugs whose safety and efficacy
are affected by gene variations

30. 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.

31. • 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

32. 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.

34. • Tamoxifen:
• ER+ breast cancer
• CYP2D6*4 --- Poor metabolizer(7-10%)- frequent
relapse , worse disease free survival

35. 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.

37. 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

38. PHARMACOGENOMICS IN
CLINICAL TRIALS

39. 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

40. 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.

43. 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.

44. • 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.

45. THANK YOU