Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Pharmacogenetics
Dr. Prashant Shukla
Junior Resident
Dept of Pharmacology
Contents
Background & Introduction
Importance & Goals of Pharmacogenomics
Pharmacogenetic phenotypes
Pharmacogenomic tests...
Background
3
Types of Genetic Variants
 A polymorphism is a variation in the DNA
sequence that is present at an allele
frequency of 1%...
SNPs
5
A single nucleotide polymorphism (SNP), is a variation in
a single nucleotide that occurs at a specific position in...
SNPs types
6
SNPs usually occur in non-coding regions
more frequently than in coding regions.
Non-coding SNPs in promoters...
How does genetic variation affect
drug effect?
7
Introduction
 PHARMACOGENETICS: The effect of
genetic variation on drug response,
including disposition (PK), safety,
tol...
Pharmacogenetics Pharmacogenomics
The study of genetic
basis for variability in
drug response
Use of genetic
information t...
Importance of
Pharmacogenetics
“One-size-fits-all drugs”
only work for about 60 %
of the population at best
40 % of the po...
Goals of Pharmacogenetics
11
Pharmacogenetic phenotypes
Genetic variations which affects the
drug response can be divided in 3
categories:
1. Variation...
13
CYP450s
Transferase
s
Variations affecting PK
14
 Phenotypic consequences of
the deficient CYP2D6
phenotype include
◦ increased risk of toxicit...
CYP2D6
 Debrisoquin- Sparteine oxidation type
of polymorphism:
1. AR
2. CYP2D6 dependent oxidation of debrisoquin
and oth...
CYP2C19
 AR
 Aromatic hydroxylation of anticonvulsant
mephenytoin
16
Normal “extensive
metabolizers”
( S )- mephenytoin ...
CYP2C9
17
Relative contributions of different
phase II pathways
18
Variations affecting PK
Suxamethonium and
Pseudocholinesterase
deficiency
Genes affecting NAT2
Polymorphism of the
TPMT (t...
Pharmacogenetics
and drug receptor
targets
Inactivation of MTHFR
Serotonin receptor
polymorphism
Beta receptor
polymorphis...
Polymorphism- modifying
diseases
 MTHFR polymorphism is linked to homocysteinemia,
which in turn affects thrombosis risk....
Clinically available
Pharmacogenomic tests
22
23
A pharmacogenetic trait is any measurable or discernible trait
associated with a drug, including enzyme activity, drug ...
METHODOLOGY
24
deCode Genetics,
Navigenics, 23andMe
WBCs/ Buccal cells
*PharmGKB
1. HLA gene tests
a) ABACAVIR & HLAB*5701
b) ANTICONVULSANTS & HLAB*1502
c) CLOZAPINE & HLA-DQ 1*0201
2. Drug metabolism r...
3) Drug target related gene test
a) Trastuzumab & HER 2
b) DASATINIB, IMATINIB & BCR-ABL 1
4) Combined (metabolism & targe...
Amplichip
•Determine the genotype of the
patient in terms of two CYP450
enzymes: 2D6 and 2C19
•FDA approved the test on De...
Pharmacogenetics
& Drug development
28
29
Key players
Role of pharmacogenetics in drug development
1. Can indentify new targets. For eg.
a) Genome wide assessment could identif...
2) Pharmacogenetics may identify subsets of
patients who will have a very high or a very low
likelihood of responding to a...
• Pharmacogenetic data can be submitted to FDA
during IND & NDA application.
• If pharmacogenetics studies on animals are
...
• Chemogenomics, or chemical genomics, is the
systematic screening of targeted chemical
libraries of small molecules again...
Pharmacogenetics
in clinical practice
34
• Three major types of evidence that should
accumulate to implicate polymorphism in clinical
care.
1. Screens of tissues f...
• Despite considerable research activity,
pharmacogenetics are not yet widely utilized in
clinical practice.
• Dose adjust...
• Another hurdle in the path of Pharmacogenetics is
Genetic Discrimination.
• Genetic discrimination occurs if people are
...
Genetic Information Non-
discrimination Act (GINA) 2008
 It is a new federal law that protects
Americans from being treat...
Advantages of
pharmacogenomics
 To predict a patient’s response to drugs
 To develop “customized” prescriptions
 To min...
Advantages of
pharmacogenomics…
 To improve the accuracy of
determining appropriate dosage of
drugs
 To screen and monit...
Barriers of
Pharmacogenomics
1. Complexity of finding gene variations
that affect drug response.
 Millions of SNPs must b...
Barriers of
Pharmacogenomics...
3. Educating healthcare providers and
patients
 Complicates the process of
prescribing an...
Barriers of
Pharmacogenomics..
4. Disincentives for drug companies to
make multiple pharmacogenomic
products
 Most pharma...
• Pharmacogenomics is in early stages of
development.
• Much of the excitement regarding the promise of
human genomics hop...
46
Clinomics
 Clinomics is the study of genomics
data along with its associated clinical
data.
 As personalized medicine ad...
• Pharmacogenomics has great potential to optimize
drug therapy.
• Newer molecular diagnostic test will have to be
develop...
Scope of Pharmacogenomics
49
50
References
51
[1]Relling MV, Giacomini KM. Pharmacogenetics Brunton
Laurence, Chabner Bruce, Knollman Bjorn, editors.
Good...
References…
[5]http://www.fda.gov/downloads/regulatoryinformat
ion/guidances/ucm126957.pdf
[6]http://www.fda.gov/downloads...
53
54
55
Upcoming SlideShare
Loading in …5
×

Pharmacogenetics and Pharmacogenomics

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.

  • Be the first to comment

Pharmacogenetics and Pharmacogenomics

  1. 1. Pharmacogenetics Dr. Prashant Shukla Junior Resident Dept of Pharmacology
  2. 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. 3. Background 3
  4. 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. 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. 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. 7. How does genetic variation affect drug effect? 7
  8. 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. 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. 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. 11. Goals of Pharmacogenetics 11
  12. 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. 13 CYP450s Transferase s
  14. 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. 15. CYP2D6  Debrisoquin- Sparteine oxidation type of polymorphism: 1. AR 2. CYP2D6 dependent oxidation of debrisoquin and other drugs impaired 3. 15
  16. 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. 17. CYP2C9 17
  18. 18. Relative contributions of different phase II pathways 18
  19. 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. 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. 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. 22. Clinically available Pharmacogenomic tests 22
  23. 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. 24. METHODOLOGY 24 deCode Genetics, Navigenics, 23andMe WBCs/ Buccal cells *PharmGKB
  25. 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. 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. 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. 28. Pharmacogenetics & Drug development 28
  29. 29. 29 Key players
  30. 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. 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. 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. 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. 34. Pharmacogenetics in clinical practice 34
  35. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 45. 46
  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. 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. 48. Scope of Pharmacogenomics 49
  49. 49. 50
  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. 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 52
  52. 52. 53
  53. 53. 54
  54. 54. 55

    Be the first to comment

    Login to see the comments

  • KaviyaUdaya

    Aug. 18, 2020
  • drmaheshkharade

    Sep. 10, 2020
  • AqsaRajpoot4

    Oct. 11, 2020
  • NavyaAntony2

    Oct. 13, 2020
  • shejaltupe

    Oct. 16, 2020
  • ZebAkhtar

    Oct. 26, 2020
  • SairaBanuShaik

    Nov. 21, 2020
  • CarolSwu

    Nov. 27, 2020
  • DianaOseko

    Dec. 28, 2020
  • ssuser18b904

    Jan. 28, 2021
  • nandhinipodamekala

    Feb. 18, 2021
  • AkritiRai9

    Feb. 27, 2021
  • EssamAlnogha

    May. 1, 2021
  • KALYANIGAWANDE6

    May. 4, 2021
  • alomariplus

    May. 29, 2021
  • DrAnusha2

    Jun. 5, 2021
  • AnubhaMagline

    Jun. 15, 2021
  • ChonglekKoh

    Jun. 22, 2021
  • SudeepPal4

    Jun. 23, 2021
  • SReddy27

    Jun. 23, 2021

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.

Views

Total views

32,725

On Slideshare

0

From embeds

0

Number of embeds

23

Actions

Downloads

1,542

Shares

0

Comments

0

Likes

132

×