Pharmacogenomics- a step to personalized medicines

1. Pharmacogenomics

2. Content
01
02
03
04
05
Introduction
Polymorphism
Predicting prescribing
Advantage of pharmacogenomics
How does genetic factors drug response?
Factors affecting drug response
06
07 Polypharmacy
08 Application
09
10
Methodology
11
Limitation
Personalised medicine

3. Introduction

4. Pharmacogenomics
Pharmacogenomics aims to develop rational means to
optimize drug therapy, with respect to the
patients' genotype, to ensure maximum efficiency with
minimal adverse effects
Pharmacogenomics is thestudy of the role of
thegenomein drug response.

5. Genomics vs. Genetics
PharmacogeneticsPharmacogenetics
•Pharmacogenomics is the use of
genetic information to guide the choice
of drug and dose on an individual basis.
•Broader term, which studies how all of
the genes (the genome) can influence
responses to drugs
•Pharmacogenetics is often a study of the
variations in a targeted gene, or group of
functionally related genes for variability
in drug response
•Refers to how variation in one single
gene influences the response to a single
drug

6. Factors
affecting drug
response

7. It is well recognized that different patients respond in different ways
to the same medication.
20 to
95%
•Genetics can account for 20-95 percent of
variability in drug disposition and effects.
•Mainly due to sequence variants in genes
encoding drug-metabolizing enzymes, drug
transporters, or drug targets
GENETIC
•Age
•Gender
•Ethnicity
•BMI
•Co morbidity
•Family history
•Circadian
rhythm
•Placebo
effect
GENETIC
•Genome
•Transcription
•Proteome
•Metabolome
•Epigenome
•Microbiome
ENVIRONMENTAL
•Nutrition
•Drugs (drug- drug
interactions)
•Chemical exposures
lifestyles
•Circadian rhythm
•Epigenome
•Compliance and
adherence

8. Indels
SNPs
Polymorphism
>1%
<1%
SNP variation is present to some appreciable
degree within a population
Indels are much less frequent in the genome
and are of low frequency
A polymorphism is a variation in the DNA
sequence that is present at an allele frequency of
1% or greater in a population.
Two major types of sequence variation are:
Single nucleotide polymorphisms (SNPs)
Insertions/deletions (indels).

9. 75%
23%
2%
A single nucleotide polumorphism (SNP), is a variation in a single
nucleotide that occurs at a specific position in the genome

10. C G T A A A T G A C C G T A C A T G A C
I I I I I I I I I I I I I I I I I I I IPresent drug
Pharmacogenomic drug
Non varient SNP varient
Protein (drug target) Protein (drug target)
Normal gene SNP gene

11. How does genetic variation affect drug effect?
Genetic polymorphism
Pharmacodynamic
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic
Receptor
Immunity
Ion-channel
Enzymes

12. Pharmacogenomictesting targets particular biomarkers that pertain to a specific class of medication. In doing so, it is possible
to determine areas in which drugs aremost likely to beeffective.
Step 1
Step 2
Step 3
Step 4When medications are
consumed, their
components are
metabolized by enzymes
But genetic differences
can create subtle
changes that alter how
these pathways work.
For this reason, a
medication that works
for one person may
have radically different
effects on another.
In theory, these pathways
would function in the
same way in all humans,

13. Most people
metabolize drug
quickly.
Others
metabolize the
drug slowly
No genetic variant
A small portion
metabolize the drug
poorly.
Normal dose
One genetic
variant
Two genetic variants
Doses need to be high
enough to treat them
effectively
Need lower doses to
avoid toxic side
effect of drug
They have higher
chances of serious
side effects
Dose for poor
metabolizer

14. Predicting
prescribing

15. Moderate cases
•Extensive metabolizer:
Individuals who have two
normal genes metabolize a
drug normally;
•Intermediate metabolizer:
Patients may have one
active and one non-active
allele for the same gene
and show reduced
metabolic activity
Extreme cases
•Ultra-rapid metabolizer:
These individuals may have
multiple copies of active genes
and have substantially increased
metabolic activity;
•Poor metabolizer:
Patients with two non-functional
genes metabolize a drug very
slowly compared to a normal
individual
Patient genotypes are usually categorized into the following predicted
phenotypes

16. Drug neither beneficial nor toxic
Drug beneficial buttoxic
Drug beneficial andnot toxic
1 2
3 4
Drug not beneficialand toxic
Patient group
receiving same
drug and
treatment
Rx

17. Major drugs ineffective for many
Cholesterol drugs
statin
Asthma drugs
Beta 2 agonist
Anti Depressants Hypertension
drugs
Heart failure drugs
10-30%40-70% 20-50%30-70% 15-25%

18. Advantage of pharmacogenomics

19. To predict a patients response to drugs
To develop customized prescriptions
To minimize or eliminate adverse events
To improve efficacy and patient compliance
To improve rational drug development
To develop more powerful, safer vaccines
To allow improvements in drug research and development (R&D) and the approval
of new drugs
To improve the accuracy of determining appropriate dosages of drugs
To screen and monitor certain diseases

20. Polypharmacy

21. A potential role pharmacogenomics may play would
be toreduce theoccurrence of polypharmacy.
It is theorized that with tailored drug treatments,
patients will not have the need to take several
medications that are intended to treat the same
condition.
A
B
C Minimize the occurrence of ADRs
Improved treatment outcomes,
Save costs by avoiding purchasing extraneous
medications,

22. 52%
Decrease in
hospital
readmission.
42%
Reduction
in ER visits
82%
Decrease in
mortality.
$4,382
Savings
per
patients in
60 days

23. Applications

24. In cardiovascular disorders,
the main concern is
response to drugs
including warfarin, clopidogr
el, beta blockers, and statins
Cardiology
Pharmacogenomics tests
are used to identify
which patients are most
likely to respond to
certain cancer drugs.
Oncology
Psychiatry
Pharmacogenomics can be used
to determine the cause of death
in drug-related deaths where no
findings emerge using autopsy
Forensic Pathology
In psychiatry, research has
focused particularly on 5-
HTTLPR and DRD2.
Pain management

25. Drugs where
pharmacogenomics
testing has clinical
significance

26. Drug class Individual drug Polymorphism
Anticoagulant Warfarin CYP2C19/VKORC1
Antineoplastic drugs Irinotecan UTG1A1
6-Mercaptopurine TPMT
Thiopurine, Azathioprine TPMT
Tamoxifen CYP2D6
Antidepressants Amitryptyline/nortryptyline CYP2C19/CYP2D6
Nortriptyline CYP2D6
Narcotic analgesic Codeine CYP2D6
Tramadol CYP2D6
Immunosupprassant Tacromilus CYP3A5

27. Methodology
Step 1
Physicians orders
pharmacogenomic
test Step 4
Run
pharmacogenomic
test on specimen
Step 2
Collect specimen
(WBC/ Buccal cells)
Step 3
Send to
laboratories
Step 5
Analyze data and
generate report
Step 6
Physician reviews
test result with
patients

28. Various types of test

29. 1)HLA gene test
a)ABACAVIR & HLAB*5701
b) ANTICONVULSANTS & HLAB*1502
c)CLOZAPINE & HLA-DQ 1*0201.
2) Drugmetabolism related gene test
a)THIOPURINE & TPMT
b) 5-FLUOROURACIL (5-FU) & DPYD
c) TAMOXIFEN & CYP2D6
d)IRINOTECAN & UGT1A1*28

30. 3) Drugtarget related gene test
a)Trastuzumab & HER 2
b)DASATINIB, IMATINIB & BCR-ABL 1
4) Combined (metabolism & target) gene test
a) WARFARIN & CYP2C9 + VKORC 1 GENOTYPING

31. Determines the genotype of
patient in terms of two CYP 450
enzymes: 2D6 and 2C19.
FDA approved the test on
December 24, 2004. The
amplichip CYP450 test is the
first FDA approved
pharmacogenetic test
Amplichip

32. Technologies andmethodsthatused in pharmacogenomics:
01
02
03
04
Pyro-sequencing
DNA microarray
Mass spectrometry
Fluoroscence based-platform
05 RFLP and RTPCR and their
types
A-C-G-T

33. Role of
pharmacogenomics in
drug development

34. •Pharmacogenomics may
contribute to a smarter drug
development process
•Allow for the prediction of
efficacy / toxicity during
clinical development
•Make the process more
efficient by decreasing the
number of patients required to
show efficacy in clinical trials
•Decrease cost & time to bring
drug to market
80% ofproductsthat
enterthe development
pipeline FAIL tomake it to
market
.

35. Necessary action to
advancement of
pharmacogenomics
in the future

36. Create profiles of diagnostic
markers and laboratory
tests.
Preparing profiles of
the SNP.
Preparing profiles
related to sensitivity of
the pharmaceutical, food
and other external
factors.
The appropriate design of
drugs
Determination of the
location of the cell and
function of proteins and
metabolic pathways in
different cell lines.
Preparing profiles of
ethnic diversity and
racial

37. Limitations

38. Insufficient validation of study
results
Identification of small inter-
individual variation in everyone’s
gene is very difficult
Expensive & Ethical issues
Many genes are involved in drug action, making
the drug target is very difficult

39. Personalised
medicine

40. Reality of the added
complexity of additional
testing & need for
interpretation of results
to individualized dosing
has been ignored.
04
It refers to approach of clinical
practice where a particular
treatment is not choosen based on
the average patient”. but on
characteristic of an individual
patient .
Pharmacogenomics
is in early stages of
development..
Much of the excitement
regarding the promise of
human genomics hopes on the
“PERSONALIZED MEDICINE OR MAGIC
BULLETS”.

41. Easy to change
colors, photos and
Text.
Drug response
phenotype.
Pharmacogenomics
Genetic
data.
Education of
professional
Privacy
issues
Personalised
medicines
Environmental
factors.
Health
care costs
Insurance issues

42. Scope
Prescription made same
for all patients
Prescription made according to
specific genes.
30-60%
Respond to drugs
100%
Respond to drugs

43. Conclusion
Pharmacogenomics has great
potential to optimize drug therapy
Newer molecular diagnostic
test will have to be develop to
detect polymorphisms
Pharmacotherapeutics decisions
will soon become fundamental for
diagnosing the illness & guiding
the choice & dosage of
medications.

44. Reference
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45. Thank you