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

1. Pharmacogenomics
Dr Manukumar

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. 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. History
1930s, Inability to taste phenylthiocarbamide
and an autosomal recessive trait
1950s , A deficiency in plasma cholinesterase
activity an inherited abnormality of
succinylcholine metabolism.
Drug induced haemolysis, Glucose-6-phosphate
dehydrogenase deficiency.(Africans)

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. 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. 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. 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. Human genetics
• Monogenic inheritance
 Bimodal
 Multimodal
 Broad
• Polygenic inheritance

12. DRUG
DRUG DRUG
METABOLIZING
TARGETS TRANSPORTERS
ENZYMES
PHARMACODYNAMICS PHARMACOKINETICS
Variability in
Efficacy/Toxicity

13. Genetic polymorphism in drug
targets
• Warfarin- Vit K epoxide reductase -VKORC1 --
A41S, R58G, V66M, L128R and V45A
• ADRB2 gene- Beta receptors – Arg16/Arg16

15. 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

16. Genetic polymorphism of drug
metabolizing enzymes
• Enzymes involved in drug metabolism

17. CYP2D6*
• Metabolism of approximately 20-25% of marketing
drugs. Beta-blockers, antidepressants,
antiarrhythmic, antipsychotics
The Pharmacogenomics Journal (2005) 5, 6–13

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

19. Selective substrates of CYP2D6

20. • Antidepressant
• in PM- users of TCA the risk of switching to
any other antidepressant within 45 days,
• UM- therapeutical failure

21. CYP2C19
• CYP2C19*2, CYP2C19*3-- poor metabolizer
Pharmacogenomics (2007) 8(9), 1199–1210

22. 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.

23. CYP2C9

24. 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

25. 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.

26. 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.

27. 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

28. 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

30. • 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.

31. • SLC21A6 gene encodes OATP-C, a liver-specific
transporter important for hepatic uptake of a
variety of endogenous and therapeutic
compounds.

32. 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.

33. 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.

34. • 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

36. Drug hypersensitivity
Drugs
The hypersensitivity was strongly
Abacavir associated with the HLA polymorphism
HLA-B*5701
CBZ-induced hypersensitivity reactions
Carbamazepine were also associated with a TNF
promoter polymorphism 308TNF
polymorphisms in 5q33 represent
Asparaginase inherited variation in the risk of
asparaginase allergy, and drug allergy and
asthma

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

39. Potential of Pharmacogenomics

40. • In today's world, only 30-60% of drugs work effectively to rid
a patient's illness.
• However, with the application of pharmacogenomics, the
success rate of drugs will increase to 100% (responders)

41. APPLICATIONS IN DRUG
DEVELOPMENT

42. 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

43. 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

44. • 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

45. Cont… PGs in drug development
Imatinib inhibit BCR-ABL tyrosine kinase
Mutations T315I and F359V directly
affect the contact between Imatinib and
the ABL kinase domain-> drug resistance
Nilotinib, Nasatinib

47. FDA issued a black box notice
clopidogrel

48. Drugs Mechanism of action Indications
Trastuzumab , 1998 HER2/neu receptors Breast CA with HER2 over
expression
Imatinib , 2001 BCSR-ABL tyrosine kinase CML, GIST
Gefitinib, 2003 EGFR tyrosine kinase Locally advance NSCLC,
domine with EGFR expression
Irinotecan 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

49. Barriers
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

50. 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”

51. 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

52. Thank you