pharmacogenomicspptnsu-191212202112

1. Pharmacogenomics

2. Content
1. Introduction
2. Factors affecting drug response
3. Polymorphism
4. How does genetic factors drug response?
5. Predicting prescribing
6. Advantage of pharmacogenomics
7. Polypharmacy
8. Application
9. Methodology
10 Limitation
11 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
Pharmacogenomicsisthestudyoftheroleof
thegenomeindrugresponse.

5. Genomicsvs.Genetics
Pharmacogenetics
•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
in drug response
Pharmacogenetics
•Pharmacogenetics is often a study of the
variations in a targeted gene, or group of
functionally related genes for variability
•Refers to how variation in one single
gene influences the response to a single
drug

6. Factors
affecting
drug
response

7. 20 to
95%
It is well recognized that different patients respond in different ways
to the same medication.
•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
ENVIRONMENT
AL
•Nutrition
•Drugs (drug- drug
interactions)
•Chemical exposures
lifestyles
•Circadian rhythm
•Epigenome
•Compliance and
adherence

8. Indels
SNPs
Polymorphism
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).
>1%
SNP variation is present to some appreciable
degree within a population
<1%
Indels are much less frequent in the genome
and are of low frequency

9. 75%
23%
2%
Asingle 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
I I I I I I I I I I
C G T A C A T G A C
I I I I I I I I I I
Presentdrug
P
harmacogenomicdrug
Nonvarient SNPvarient
Protein (drug target) Protein (drug target)
Norm
a
l gene SNPgene

11. Howdoesgeneticvariationaffectdrugeffect?
Genetic polymorphism
Pharmacodynamic
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetic
Receptor
Immunity
Ion-channel
Enzymes

12. Pharmacogenomictestingtargetsparticularbiomarkersthatpertaintoaspecificclassofmedication.Indoingso,itispossible
todetermineareasinwhichdrugsaremostlikelytobeeffective.
Step1
Step2
Step3
Step4
When 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. Other
s metabolize
the drug
slowly
Nogeneticvariant
Normaldose
One
genetic
variant
T
wogeneticvariants
Most
people
metabolizedrug
quickly.
Doses need to be high
enough to treat them
effectively
Need lower doses to
avoid toxic side
effect of drug
Asmallportion
metabolizethedrug
poorly
.
They have higher
chances of serious
side effects
Doseforpoor
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. Drugneitherbeneficialnortoxic
Drugbeneficialbuttoxic
Drug beneficialandnot toxic
Drugnotbeneficialandtoxic
Patient group
rec1
eivin2
g same
drug and
t
3
reatm
4
ent
Rx

17. Major drugs ineffective for many
AntiDepressants Heartfailuredrugs
Hypertension
drugs
10-30%
Asthmadrugs
Beta2agonist
40-70% 20-50%
Cholesterol
drugs statin
30-70% 15-25%

18. Advantage of pharmacogenomics

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

20. Polypharmacy

21. Apotentialrolepharmacogenomicsmayplaywould
betoreducetheoccurrenceofpolypharmacy
.
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 MinimizetheoccurrenceofADRs
Improvedtreatmentoutcomes,
Savecostsbyavoidingpurchasingextraneous
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. Cardiology
In cardiovascular disorders,
the main concern is
response to drugs
including warfarin, clopidogr
el, beta blockers, and statins
Oncology
Pharmacogenomics tests
are used to identify
which patients are most
likely to respond to
certain cancer drugs.
Forensic Pathology
Pharmacogenomics can be used
to determine the cause of death
in drug-related deaths where no
findings emerge using autopsy
Psychiatry
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
Step1
Physicians orders
pharmacogenomic
test Step4
Run
pharmacogenomic
test on specimen
Step2
Collect specimen
(WBC/ Buccal cells)
Step3
Send to
laboratories
Step5
Analyze data and
generate report
Step6
Physician reviews
test result with
patients

28. Varioustypesoftest

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

30. 3)Drugtargetrelatedgenetest
a)Trastuzumab & HER 2
b)DASATINIB, IMATINIB & BCR-ABL1
4)Combined(metabolism&target)genetest
a) WARFARIN & CYP2C9 + VKORC 1 GENOTYPING

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

32. Technologiesandm
e
thodsthatusedinpharm
acogenomics:
01 DNA microarray
02
03
04
Pyro-sequencing
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
efficient
the process more
by decreasing the
number of patients required to
show efficacy in clinical trials
•Decrease cost & time to bring
drug to market
80%ofproductsthat
enterthedevelopment
pipelineFAILtom
akeitto
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
location
function
metabolic
proteins
pathways
of the
of the cell and
of and
in
different cell lines.
Preparing profiles of
ethnic diversity and
racial

37. Limitations

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

39. Personalised
medicine

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

41. 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.
Respond to drugs
30-60%
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
1.
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3.
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5.
6.

45. Thankyou