Pharmacogenomics is a new trending branch which has created enormous hopes in improving diagnostic methods, treatment outcomes and preventing adverse events and therapeutic failures. In this ppt basics of pharmacogenomics and pharmacogenetics has been discussed in simplest possible way along with two case studies. Clinical applications of pharmacogenomics has also been discussed in brief.

1. Pharmacogenomics
Dr.Kiran A. Kantanavar
Department of Pharmacology
KSHEMA, Mangaluru.
kirankantanavar@gmail.com

2. Introduction
“Pharmacogenetics is the study of the genetic
basis for variation in drug response.”
“Pharmacogenomics involves the study of role
of genes and their variations in the molecular
basis of the disease and therefore the resulting
pharmacologic impact of drugs on that disease”

3. Adequate
therapeutic
response
No response
Adverse effect

4. Factors contributing to variation in
drug response
• Diet
• Age
• Gender
• Lifestyle
• Circadian & seasonal
variation
• Exercise
• Comorbidities
• Renal and hepatic
function
• Genetic factors

5. Genetic polymorphisms

6. Genetic polymorphisms
Single nucleotide
polymorphisms (SNPs)
•Coding, nonsynonymous
CCG – Pro
CAG – Gln
•Coding, synonymous
CCG – Pro
CCA – Pro
•Non coding
Indels
•Insertions/deletions
•Copy number variations
oGene duplications
oLarge deletions

8. Adequate therapeutic response
Pharmacokinetic properties
• Absorption
• Distribution
• Metabolism
• Excretion
Pharmacodynamic properties
• Receptors
• Enzymes
• Ion channels
• Transporters

9. Genetic polymorphism in drug
transport
• P-Glycoprotein multidrug transporter (MDR1)
• Vincristine, vinblastine, doxorubicin,
daunorubicin
• MDR1 – major cause for Low drug level in cells

10. Genetic polymorphisms in drug
metabolism
• CYP2D6
– Tricyclic antidepressants
• Poor metabolisers – high
plasma concentration – toxic
effects
• Rapid metabolisers – low
plasma concentrations –
therapeutic failure
– Codeine (as analgesic)
• Poor metabolisers –
therapeutic failure

11. Genetic polymorphisms in drug
metabolism
• CYP2C9
– Warfarin – slow metabolism – high risk of bleeding
• CYP2C19
– Clopidogrel
• Loss of function alleles – decreased activation of
clopidogrel

13. Gene product Drugs Responses affected
CYP2C9
Warfarin, Tolbutamide, Phenytoin,
NSAIDs
Anticoagulant effect of warfarin
CYP2C19
Omeprazole, clopidogrel,
mephenytoin, propranolol
Peptic ulcer response to
omeprazole, Cardio-vascular
events after clopidogrel
CYP2D6
Beta blockers, codeine,
antidepressants, tamoxifen
antipsychotics, debrisoquine,
Codeine efficacy,
Tardive dyskinesia from
antipsychotics
CYP3A4/A5/A7
Macrolides, cyclosporine,
tacrolimus, CCBs, etc
Efficacy of immunosuppressive
effect of tacrolimus
UGT1A1 (UDP
glucuronosyl
transferase)
Irinotecan, bilirubin Irinotecan toxicity
Thiopurine methyl
transferase (TPMT)
Mercaptopurine, thioguanine,
azathioprine
Thiopurine toxicity and efficacy
Dihydropyramidine
dehydrogenase
Fluorouracil, capacitabine 5-fluorouracil toxicity

14. Case study
• A 72 year old male with metastatic colorectal
cancer was prescribed an anticancer drug
Irinotican 180mg/m2, as an intravenous
infusion, which was repeated every 2weeks,
along with several other chemotherapeutic
agents.
• Liver function and renal function were normal.
• Blood samples were drawn.

15. • After the treatment cycle, the patient experienced
very severe neutropenia and diarrhea.
• Plasma levels of SN-38, the active metabolite of
irinotecan, were 4fould higher than those found in
most patients.
• The irinotecan dose was reduced by 50%.
• Plasma levels of SN-38 were lower but still more
than twice normal.
• However after 2nd cycle, there was no neutropenia
and only grade 1 diarrhea.
• CT and MRI scan showed partial response to the
chemotherapy.

16. Case study answer
• Irinotecan is metabolized to the active
cytotoxic molecule SN-38, which is also
responsible for toxicity.
• Inactivation of SN-38 occurs via the
polymorphic UGT1A1 enzyme.
• Carriers of the UGT1A1*28 variant have
reduced enzyme activity.

17. Genetic polymorphisms in drug targets
• Beta adrenergic receptors
– 389th position
Arginine Glycine
Metoprolol
Marked fall
in BP
Moderate
fall in BP

18. Targets & receptors Drugs Responses affected
Angiotensin converting
enzyme
ACE inhibitors eg:
Captopril, enalapril etc
Renoprotective effect,
hyptension, cough
Dopamine recetors (D2,
D3, D4)
Antipsychotics –
haloperidol, clozapine,
thioridazine
Antipsychotic induced
tardive dyskinesia, acute
akathesia,
hyperprolactinemia in
females
Ion channels (HERG,
KvLQT1, Mink, MiRP1)
Erythromycin, cisapride,
clarithromycin, quinidine
Increased risk of drug
induced torsdes de pointes
and QT interval
Serotonin transporters
Antidepressants –
clomipramine, fluoxetine,
paroxetine, fluoxemine
Clozapine effects, 5-HT
neurotransmission,
antidepressant response

19. PHARMACOGENOMICS
IN
CLINICAL PRACTICE

20. Assess patient’s genetic makeup and depending on the
results use appropriate medications
Identify genetic polymorphisms that are responsible for
therapeutic effect or adverse effect
(database)
Identify genes in the drug response pathway

22. • Clinical pharmacogenomics implementation
consortium (CPIC) – 2009
• Guidelines for many gene–drug pairs
– HLA-B - abacavir, carbamazepine
– CYP2D6 - codeine
– CYP2C9, VKORC1 - warfarin
– UGT1A1 - irinotecan
– CYP2C19 - clopidogrel
Clinical practice guidelines

23. Clinical practice guidelines
• International Warfarin Pharmacogenetics
Consortium (IWPC)
– Algorithm to estimate warfarin dosing

24. P G S
H E C
A N R
R E E
M T E
A I N
C C I
O N
G

25. Pharmacogenitic screening
Direct sequencing
• Gene of interest
• Easy
• Cost is less
Whole genome sequencing
• One time procedure for an
individual
• Can be stored in genetic
library and information can
be used whenever
necessary
• Polymorphism in all genes
can be identified

26. Pharmacogenitic screening tests
AmpliChip CYP450
Detects polymorphism in drug metabolizing
enzymes (DMEs) such as CYP2D6, CYP2C19
Affymetrix DMET
Detects polymorphism in DMEs – CYP1A2,
CYP2C9, CYP2C19, CYP2D6, CYP3A4 A5 & A7 and
transporters
PHARMAChip
Detects polymorphisms in CYP450 enzymes and in
genes that code for drug receptors, transporters
and other targets
Therascreen Kit For use of afatinib in non-small-cell lung cancer
Cobas EGFR Mutation
Test
For use of erlotinib in non-small-cell lung cancer

27. Case study
• The patient is a 65 year old widowed white female who presented
complaining of “doctors not doing their job to fix me.”
• Psychiatric history: diagnosis from prior psychiatrists include
Major depressive disorder (recurrent, severe),
Dysthymic disorder,
Personality disorder NOS and
Narcissistic personality disorder.
• Medical history: essential hypertension and hypercholesterolemia

28. • Previous medication trials: she has tried many psychotropic
medications in the past such as
fluoxetine (Prozac®),
escitalopram (Lexapro®),
nortriptyline (Pamelor®) and
bupropion (Wellbutrin®)
as monotherapy
in addition to a few augmentation strategies such as adding
aripiprazole (Abilify®) and
quetiapine (Seroquel®)
• Medications at the time of GeneSight testing:
nortriptyline (Pamelor®) 50 mg PO QHS,
aripiprazole (Abilify®) 5 mg PO QHS,
atorvastatin (Lipitor®) 20 mg PO QHS, and
lisinopril (Zestril®) 20 mg PO QAM.

33. Conclusions
• Individualized medicine based on personal
genotypes remains a glimpse at the future.
• It will not be long before the personalized
information provided through genetic databases
is applied to the mainstream of the health care
system.
• High cost and Ethical concerns for privacy - major
challenges.
• Constructive efforts from scientists, clinicians,
ethicists and heath care managers can bring
change in the lives of patients.

34. For more discussion on pharmacogenomics
Contact – kirankantanavar@gmail.com

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