pharmacogenomics

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
TARGETS
DRUG
METABOLIZING
ENZYMES
DRUG
TRANSPORTERS
PHARMACOKINETICS
PHARMACODYNAMICS
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
• 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.
14%
11%

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

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

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
• .
.
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

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
domine
Locally advance NSCLC,
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