pharmacogenomics with examples and applications

1. PHARMACOGENOMICS
Sanju k
Department of pharmacology
KMCH college of pharmacy.

2. • Pharmacogenomics is the study that examines how
genetic variations affect the ways in which people
respond to drugs.
• Pharmacogenomics examine many genomic loci
including large biological pathways to determine the
variability.
• Pharmacogenetics focuses on large clinical effects of
single gene variant in small number of patients.

3. Merits and demerits
MERITS
• Improve drug safety, and reduce ADRs;
• Tailor treatments to meet patients' unique
genetic pre-disposition, identifying optimal
dosing;
• Improve drug discovery targeted to human
disease; and
• Improve proof of principle for efficacy trials.

4. Demerits

5. • Polymorphism
Natural variations in a gene ,DNA sequence or
chromosome that have no adverse effects on the
individual.
• Allele
• An allele is one of a pair of genes that appear at a
particular location on a particular chromosome
and control the same characteristic.

6. PHARMACOGENOMICS IN DRUG
DISCOVERY AND DEVELOPMENT
• Through examination of individual response profiles and
elucidation of different effect of different compounds on
gene expression will lead to target identification,drug
discovery and compound selection.
 Identification of novel proteins involved in disease
processes
 Targetting of proteins with variant structure resulting
from genetic polymorphism.
 Refinement of existing targets to improve specificity of
drug action.

7. Approaches to drug discovery and
development
• Development of new drugs to overcome drug
resistance or target new drug targets.
• Optimisation of drug metabolism and
pharmacokinetics(DMPK) to minimise
variations in drug levels

8. Overcoming drug resistance
• Imatinib >>nilotinib>>nasatinib
Drug Target Mutation sites Effect
Imatinib BCR-ABL tyrosine
kinase,mast/stem
cell growth factor
receptor(SCFR,CD1
17),PDGFR
T315I,F359V(contac
t regions of drug
with ABL domain),
P-loop of ATP
binding pocket of
kinase
domain(suitable
conformation for
binding)
25% of patients
with
gastrointestinal
stromal tumors
suffered relapse.

9. Optimisation of DMPK
• DMPK optimisatisation is a practical and effective
approach in developing especially orally active drugs
that have predcatable pharmacokinetic profiles and
can be administered with reduced need for
monitoring and dose adjustment in drug therapy.
Eg:oral anticoagulants
• Warfarin>> clopidogrel>>prasugrel>>apixaban

10. Drug Target Variation causing
factor
Drug
intermediates
Effect
warfarin VKORC1 CYP2C9 hypersensitation or
true resistance
CLOPIDOGREL Antiplatelet
and factor Xa
CYP influenced
Hepatic carboxyl
esterases
deactivates active
thiol intermediate
(CYP2C19(2ox
o),CYP3A4(
active thiol))
Lesser degrees of
platelet inhibition and
increased risk of
cardiovascular events
in esterase over
expressed population
PRASUGREL Antiplatelet
and factor Xa
Esterase(less
variant)
CYP3A4 Greater platelet
aggregation with
lesser variability

12. Pharmacogenetics in practice
• In a large population a medication that is proven
efficacious in many patients often fails to work in
some other patients.
• Major genetic factors affecting individual drug
response include
Therapeutic targets
Drug metabolising enzyme
Drug transporters
Targets of ADR

13. Therapeutic target
Eg1: warfarin
C1173T polymorphism in
intron 1 of VKORC1 result in
dose change from 15mg/day
to 16mg/day

14. Eg2.
Anti HIV drugs:vicriviroc,maraviroc
Target associated Variants Effects
CCR2,a chemokine
receptor for
monocyte chemo
attractant protein1.
Polymorphism at
codon 64 (V64I)
with Ile allele
HIV progress to
AIDS2 four years
later than those
carrying wild type
allele
CCR5,a chemokine
receptor used by
HIV as a coreceptor
to enter into the
target cell
White persons have
32 base pair
deletion but it is not
find in Africans
Deletions make
receptor
nonfunctional and
less HIV
transmission

15. Eg3 β agonist and ADRB2
Drug Gene mutation Effects
Albuterol 2 SNPs of
ADRB2 results
in mutations
R16G Q27E
Evokes a larger
and more rapid
broncho
dilation
response in
arg16/arg16
than in carriers
of gly16 allele
(arg16/gly16,gly
16/gly16)

16. Drug metabolisms
• Cytochrome P450 catalyses the mono
oxygenation of lipophilic drugs to give rise to
metabolites with altered activity and
increased water solubility
• Variable expression of genes encoding these
enzyme make effect on drug response
depending upon the affinity of the receptors
of the metabolite and orginal drug molecule.

17. Drug Enzyme involved Effect
codeine Decreased expression of
CYP2D6
Less metabolism of the
drug causes drug to
remain in circulation for
a longer time causing
respiratory side effects
warfarin Reduced CYP2C9 activity
in *2 and *3 variants
15% variability in dose
requirement
tacrolimus CYP3A5*1 variant Require larger dose to
reach targetted Co

19. CYP2D6 is the rate limiting enzyme in catalysing the conversion
of the prodrug tamoxifen into active metabolites 4-
hydroxytamoxifen and endoxifen which have significantly higher
affinity for the drug target,estrogen receptor.

21. DRUG TRANSPORTERS
• Drug transporters modulate the
absorption,distribution and elimination of
drugs by controlling the influx and efflux of
drugs
• Increasing evidence indicates genetic
polymorphism of transporters can have
profound impact on drug diposition,drug
efficacy and drug safety.

22. Drug Transporter Effect
digoxin C3435T
polymorphism of
ABCB1 gene
encoding p-gp
Reduced serum
digoxin
concentration
diflometacan ABCG2
heterozygous
genotype C421A
300% higher plasma
levels
Estrone sulfate,
estradiol 17β-D-
Glucoronide
OATP-c*9 and *5
(gene SLC21A6)
Reduced uptake

23. ABCC*2 haplotypes causes less exposure to intestinal cell by
reducing hepatibiliary secretion and thus reduce incidence of
diarrhoea

24. TARGETS OF ADR
• Idiosyncratic drug reactions characterised by their
rare occurance and requirement of multiple
exposure are most extreme of individual
variability in drug safety.
1. On target drug toxicity:inhibition or activation
of a therapeutic target eg:excessive bleeding
from high doses of warfarin
2. Off target drug toxicity: interaction between a
drug and a target protein differbt from the
therapeutic target.eg:statin induced myopathy.

25. drug gene effect
flucloxacillin HLA-B*1 attributed
to SNP in MHC
Cholestatic
hepatitis(drug
induced liver injury)
simvastatin Various(about
3lakh) at various loci
SNP associated with
SLCO1B1
myopathy
Various cardiac and
non cardiac drugs
KCNE2 encoding a
subunit of cardiac
potassium channel
Long QT syndrome
(arrhythmia –
torsades de pointes)

26. DRUG HYPERSENSITIVITY
• They are adverse effect OF DRUGS THAT
OCCUrs at a dose tolerated by typical subjects
and clinically resembles allergy.
• Eg:abacavir hypersensitivity associated with
HLA-B*5701(effective antigen presenting
molecule) polymorphism.

27. Thank you