Pharmacogenetics and pharmacogenomics is an upcoming branch in therapeutics. Various pharmacogenomic tests are currently available to aid in actual clinical practice. It has shown to have promising results in personalized medicine It is my attempt to compile the basic concepts from various books, articles, and online journals. Please feel free to comment.

1. Pharmacogenetics
Dr. Prashant Shukla
Junior Resident
Dept of Pharmacology

2. Contents
Background & Introduction
Importance & Goals of Pharmacogenomics
Pharmacogenetic phenotypes
Pharmacogenomic tests
Pharmacogenetics & Drug development
Pharmacogenetics in clinical practice
Advantages and barriers of pharmacogenomics
2

3. Background
3

4. Types of Genetic Variants
 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).
 Indels are much less frequent in the
genome and are of low frequency in 4

5. SNPs
5
A single nucleotide polymorphism (SNP), is a variation in
a single nucleotide that occurs at a specific position in the
genome, where each variation is present to some appreciable
degree within a population (e.g. >1%).
75
%
23
%
2%
*

6. SNPs types
6
SNPs usually occur in non-coding regions
more frequently than in coding regions.
Non-coding SNPs in promoters/enhancers
or in 5′ and 3′ untranslated regions may
affect gene transcription or transcript
stability

7. How does genetic variation affect
drug effect?
7

8. Introduction
 PHARMACOGENETICS: The effect of
genetic variation on drug response,
including disposition (PK), safety,
tolerability and efficacy (PD).
PHARMACOGENOMICS: It employs the
tools for surveying the entire genome to
assess multigenic determinants of drug
response. 8

9. Pharmacogenetics Pharmacogenomics
The study of genetic
basis for variability in
drug response
Use of genetic
information to guide the
choice of drug and dose
on an individual basis
9

10. Importance of
Pharmacogenetics
“One-size-fits-all drugs”
only work for about 60 %
of the population at best
40 % of the population have
increased risks of ADR
because their genes do not do
what is intended of them
10

11. Goals of Pharmacogenetics
11

12. Pharmacogenetic phenotypes
Genetic variations which affects the
drug response can be divided in 3
categories:
1. Variations affecting Pharmacokinetics
.
2. Variations affecting Drug
receptor/target.
12

13. 13
CYP450s
Transferase
s

14. Variations affecting PK
14
 Phenotypic consequences of
the deficient CYP2D6
phenotype include
◦ increased risk of toxicity of
antidepressants or
antipsychotics (catabolized by
the enzyme)
◦ lack of analgesic effect of
codeine (anabolized by the
enzyme)
 The ultra-rapid phenotype is
associated with extremely
rapid clearance and thus
decreased efficacy of
antidepressants.

15. CYP2D6
 Debrisoquin- Sparteine oxidation type
of polymorphism:
1. AR
2. CYP2D6 dependent oxidation of debrisoquin
and other drugs impaired
3.
15

16. CYP2C19
 AR
 Aromatic hydroxylation of anticonvulsant
mephenytoin
16
Normal “extensive
metabolizers”
( S )- mephenytoin is extensively hydroxylated by
CYP2C19 before its glucuronidation and rapid
excretion in the urine, whereas
( R )-mephenytoin is slowly N -demethylated to
nirvanol, an active metabolite
Poor metabolizers 1. Lack of stereospecific ( S )-mephenytoin
hydroxylase activity, so both ( S )- and ( R )-
mephenytoin enantiomers are N -demethylated
to nirvanol, which accumulates in much higher
concentrations.
2. Increase the therapeutic efficacy of omeprazole
in gastric ulcer and gastroesophageal reflux
diseases.

17. CYP2C9
17

18. Relative contributions of different
phase II pathways
18

19. Variations affecting PK
Suxamethonium and
Pseudocholinesterase
deficiency
Genes affecting NAT2
Polymorphism of the
TPMT (thiopurine
S-methyltransferase)
gene
UGT polymorphism
•Due to mutation, there is
formation of abnormal
cholinesterase.
•The individuals fail to
inactivate Suxamethonium
rapidly and experience
prolonged neuro- muscular
blockade.
•Frequency: 1/3000
19
•Rate of drug acetylation
varied in different
population as a result of
balanced polymorphism.
•Acetylation by N
acetyltransferase (NAT 2)
enzyme
•Slow acetylators:
peripheral neuropathy
•Fast acetylators:
Hepatotoxicity (wrt
Isoniazid)
•AR trait
•Rapidly degraded mutant
enzyme and consequently
deficient S -methylation of
6-MP, thioguanine, and
azathioprine, required for
their detoxification.
•High risk of thiopurine
drug-induced fatal
hematopoietic toxicity.
•Toxic side effects due to
impaired drug conjugation
and/or elimination (eg, the
anticancer drug irinotecan)

20. Pharmacogenetics
and drug receptor
targets
Inactivation of MTHFR
Serotonin receptor
polymorphism
Beta receptor
polymorphism
Polymorphism in HMG-CoA
reductase
Polymorphism in Ion
channels
Polymorphism in ACE
20
GI toxicity in case of
Methotrexate
Responsiveness to
Depression
Responsiveness to
Asthma
Degree of lipid lowering
following Statins
Cardiac arrhythmias
Renal Function Test

21. Polymorphism- modifying
diseases
 MTHFR polymorphism is linked to homocysteinemia,
which in turn affects thrombosis risk. These
polymorphisms do not directly affect the PK or PD of
prothrombotic drugs, such as glucocorticoids,
estrogens, and asparaginase, but may modify the
risk of the phenotypic event (thrombosis) in the
presence of the drug.
 Polymorphisms in ion channels (e.g., HERG,
KvLQT1, Mink, and MiRP1) increase the risk of
cardiac arrhythmias, which may be accentuated in
the presence of a drug that can prolong the QT
interval (e.g., macrolide antibiotics, antihistamines).
21

22. Clinically available
Pharmacogenomic tests
22

23. 23
A pharmacogenetic trait is any measurable or discernible trait
associated with a drug, including enzyme activity, drug or
metabolite levels in plasma or urine, effects on BP or lipid levels,
and drug-induced gene expression patterns

24. METHODOLOGY
24
deCode Genetics,
Navigenics, 23andMe
WBCs/ Buccal cells
*PharmGKB

25. 1. HLA gene tests
a) ABACAVIR & HLAB*5701
b) ANTICONVULSANTS & HLAB*1502
c) CLOZAPINE & HLA-DQ 1*0201
2. Drug metabolism related gene test
a) THIOPURINE & TPMT
b) 5-FLUOROURACIL (5-FU) & DPYD
c) TAMOXIFEN & CYP2D6
d) IRINOTECAN & UGT1A1*28
Various type of test are
25

26. 3) Drug target 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
26

27. Amplichip
•Determine the genotype of the
patient in terms of two CYP450
enzymes: 2D6 and 2C19
•FDA approved the test on Dec 24,
2004. The Amplichip CYP450 test
is the first FDA approved
pharmacogenetic test.
27

28. Pharmacogenetics
& Drug development
28

29. 29
Key players

30. Role of pharmacogenetics in drug development
1. Can indentify new targets. For eg.
a) Genome wide assessment could identify
genes whose expression differentiate
inflammatory process.
b) A compound could be identified that
can change expression of gene responsible
for inflammatory process.
c) That compound can serve as starting point
for anti inflammatory drug development.
30

31. 2) Pharmacogenetics may identify subsets of
patients who will have a very high or a very low
likelihood of responding to an agent.
a) So drug can be tested on selected patients
will respond & low possibility of ADRs.
b) This will reduce the time & cost of drug
development.
3) Pharmacogenomics can identify the subset of
patient with higher risk of serious adverse effect.
So these patients can be avoided in trials
31

32. • Pharmacogenetic data can be submitted to FDA
during IND & NDA application.
• If pharmacogenetics studies on animals are
available then pharmacogenetic tests should be
included in clinical trials.
• During NDA application sponsor should submit the
pharmacogenetic data voluntarily, intended to put
on label of the drug.
32

33. • Chemogenomics, or chemical genomics, is the
systematic screening of targeted chemical
libraries of small molecules against individual drug
target families (e.g., GPCRs, nuclear
receptors, kinases, proteases, etc.) with the ultimate
goal of identification of novel drugs and drug targets.
Chemogenomics

34. Pharmacogenetics
in clinical practice
34

35. • Three major types of evidence that should
accumulate to implicate polymorphism in clinical
care.
1. Screens of tissues from individuals linking the
polymorphism to a trait.
2. Complementary preclinical studies.
3. Multiple supportive clinical phenotype/genotype
association studies.
36

36. • Despite considerable research activity,
pharmacogenetics are not yet widely utilized in
clinical practice.
• Dose adjustment on the basis of renal or hepatic
dysfunction can be accepted by clinician.
• But there is much more hesitation from clinician to
adjust the dose on pharmacogenetic ground.
• This can be due to resistance to accept or can be
due to unfamiliarity with the principles of genetics.
37

37. • Another hurdle in the path of Pharmacogenetics is
Genetic Discrimination.
• Genetic discrimination occurs if people are
treated unfairly because of differences in their
DNA that increase their chances of getting a
certain disease.
• For example, a health insurer might refuse to give
coverage to a woman who has a DNA difference
that raises her odds of getting breast cancer .
• Employers also could use DNA information to
decide whether to hire or fire workers.
38

38. Genetic Information Non-
discrimination Act (GINA) 2008
 It is a new federal law that protects
Americans from being treated unfairly
because of differences in their DNA
that may affect their health.
 The new law prevents discrimination
from health insurers and employers.
39

39. Advantages of
pharmacogenomics
 To predict a patient’s response to drugs
 To develop “customized” prescriptions
 To minimize or eliminate adverse events
 To improve efficacy and patient
compliance
 To improve rational drug development
 Pharmacogenetic test need only be
conducted once during the life time.
40

40. Advantages of
pharmacogenomics…
 To improve the accuracy of
determining appropriate dosage of
drugs
 To screen and monitor certain
diseases
 To develop more powerful, safer
vaccines
 To allow improvements in drug
discovery and development
41

41. Barriers of
Pharmacogenomics
1. Complexity of finding gene variations
that affect drug response.
 Millions of SNPs must be identified
and analyzed to determine their
involvement in drug response
2. Confidentiality, privacy and the use
and storage of genetic information
42

42. Barriers of
Pharmacogenomics...
3. Educating healthcare providers and
patients
 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
43

43. Barriers of
Pharmacogenomics..
4. 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 hundreds of millions of
dollars on pharmacogenomic based
drug development.
44

44. • 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”.
• Reality of the added complexity of additional
testing & need for interpretation of results to
individualized dosing has been ignored.
Pharmacogenomics &
Personalized medicine
45

45. 46

46. Clinomics
 Clinomics is the study of genomics
data along with its associated clinical
data.
 As personalized medicine advances,
clinomics will be a bridge between basic
biological data and its effect on human
health.
47

47. • 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.
CONCLUSION
48

48. Scope of Pharmacogenomics
49

49. 50

50. References
51
[1]Relling MV, Giacomini KM. Pharmacogenetics Brunton
Laurence, Chabner Bruce, Knollman Bjorn, editors.
Goodman and Gillman’s The Pharmacological Basis of
Theraputics.12ed. USA: McGraw Hills; 2011.p145-68.
[2] Rang HP, Dale M M, Ritter JM, Flower RJ, Henderson
G. Pharmacogenetics, Pharmacogenomics &
Personalised medicine. Hyde Madelane, Mortimer
Alexandra, editors. Pharmacology. 7ed.Britain: Elsevier
Churchill Living stone ;2012.p132-8.
[3] http://www.genome.gov/10002077#al-2
[4]http://www.fda.gov/drugs/scienceresearch/researcharea
s/pharmacogenetics/ucm083378.htm

51. References…
[5]http://www.fda.gov/downloads/regulatoryinformat
ion/guidances/ucm126957.pdf
[6]http://www.fda.gov/downloads/Drugs/ScienceRe
search/ResearchAreas/Pharmacogenetics/ucm1
16702.pdf
[7] Semizarov D, Blomme D.Introduction genomics
& personalised medicine.Genomics in Drug
Discovery and Development .1ed. USA: Wiley;
2009.p1-24.
[8] Dr. Hemant Banga’s Seminar on
Pharmacogenetics
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