3. DEFINITIONS
• PHARMACOGENETICS: Study of the genetic basis for variation in drug
response.
• Influence of genes on efficacy and side effects of drugs.
• PHARMACOGENOMICS: (interaction of DRUGS AND GENOME) Study
of role of genes and their variations in the molecular basis of disease,
and resulting pharmacological impact of drugs on that disease.
• The study of the relationship between genetic variations and how
our body responds to medications.
4. Pharmacogenomics
• How a person’s genetic inheritance affects the body response to drug
• Intersection of pharmaceuticals and genetics
• Combines pharmaceutical science of biochemistry with knowledge of
genes, proteins and SNPs.
• Measuring DNA sequence variations and drug responses, especially
mRNA expression analysis
5.
6. DRUG RESPONSE - Factors contributing to
variation
• Diet
• Age
• Gender
• Lifestyle
• Circadian and seasonal variation
• Exercise
• Comorbidities
• Renal and hepatic function
GENETIC FACTORS
7. DRUG RESPONSE – Factors contributing
• PHARMACOKINETIC
Absorption
Distribution
Metabolism
Excretion
“what body does to drug”
• PHARMACODYNAMIC
Receptors
Enzyme
Ion Channels
Transporters
“what drug does to body”
8. DRUG RESPONSE – Individual Variation
• Individual Variability in Drug Therapy
• Factors Affecting Individual Drug response
Genetic polymorphisms of Drug Target
Genetic Polymorphisms of Drug Metabolizing Enzymes
Genetic Polymorphisms of Drug Transporters
Genetic Variables Affecting Adverse Drug Reactions
9. Implications & Applications
• Identify genes in the drug response pathway
• Identify genetic polymorphisms that are responsible for therapeutic
effect or adverse effect (Database)
• Assess patient’s genetic makeup and depending on the results use
appropriate medications
10. Implications & Applications
• Improved efficacy
• Reduced adverse reactions
• Genotype phenotype correlation
• Identify novel targets for new drugs
• To predict disease susceptibility and drug response
• Personalized therapy
11. Implications & Applications
• More powerful Medicine
• Better, safer drugs first time
• More accurate methods to determine drug dosage
• Advanced screening of disease
• Better vaccines
• Improvement in drug discovery and approval process
• Decrease in the overall cost of health
12. Pharmacogenetic 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 when needed
Polymorphism in all genes can be identified
13. Pharmacogenomics
• Platforms: Human Genome Project
• International HapMap Project
• 1000 Genome project
India
• Department of Biotechnology, Ministry of Science and Technology,
New Delhi
• Human Genetics and Genome Analysis Program
14. APPLICATIONS – a) G6PD deficiency
• the first recognized pharmacogenetic disorder, having been described
by Pythagoras around 500 BC.
• inherited as an X-linked recessive trait
• rare in Caucasians but affecting approximately 10% of Afro-Caribbean
males and relatively common in the Mediterranean
• common in these populations as a result of conferring increased
resistance to the malarial parasite.
• Sensitive - primaquine, phenacetin, nitrofurantoin, sulfonamides.
15. b) CYP450
• Cytochrome P450 enzymes are present in most tissues of the body
• function to metabolize potentially toxic compounds,
including drugs and products of endogenous metabolism such
as bilirubin principally in the liver.
• Human Genome Project identified 57 human genes coding for the
various cytochrome P450 enzymes
• Effects on CYP isozyme activity are a major source of adverse drug
interactions, since changes in CYP enzyme activity may affect
the metabolism and clearance of various drugs.
16. Genetic polymorphisms in drug metabolism :
• CYP2C9 – Warfarin – slow metabolism two variants (CYP2C9*2 and
CYP2C9*3) – high risk of bleeding – require lower doses
Phenytoin
• CYP2C19 – Clopidogral
• CYP2D6 –variation in this gene - is involved in the metabolism of
more than 20% of prescribed drugs
Anti cancer – Tamoxifen
Pain killer - Codeine
Beta blockers -metoprolol and carvedilol
Antidepressants- fluoxetine and imipramine,
Antipsychotics -thioridazine and haloperidol
17. APPLICATIONS - Isoniazid
• It is rapidly absorbed from the gut, resulting in an initial high blood
level that is slowly reduced as the drug is inactivated and excreted.
• The metabolism of isoniazid – acetylation in Liver two groups - rapid
and slow inactivators.
• three genes responsible for N-acetyltransferase activity in humans.
• NATP - one of which is not expressed and represents a pseudogene
• NAT1 - one that does not exhibit differences in activity between
individuals
• NAT2 - mutations in which are responsible for the inherited
polymorphic variation. -reported to modify the risk of developing a
number of cancers-bladder, colorectal, breast, and lung cancer. -
differences in acetylation of aromatic and heterocyclic amine
carcinogens.
18. APPLICATIONS - Isoniazid
• Rapid acetylators, blood levels of the drug
fall rapidly after an oral dose. In slow
acetylators,. - increased risk of liver damage
from isoniazid.
• Slow inactivators (blood levels remain high
for some time) - significantly greater risk of
developing side effects on doses that rapid
inactivators require to ensure adequate
blood levels for successful treatment of
tuberculosis
• Hydralazine - antihypertensive,
sulfasalazine - sulfonamide derivative used
to treat Crohn disease.
19. c) Malignant hyperthermia –
• autosomal dominant trait
• 1 in 10,000 people.
• susceptibility status requires a muscle biopsy with in vitro muscle
contracture testing in response to exposure to halothane and
caffeine.
• most common cause is a mutation in the ryanodine receptor (RYR1)
gene.
20. d) TPMT - Thiopurines
• Analyzing genetic variation within the thiopurine methyltransferase
(TPMT) gene
• encodes - enzyme responsible for methylation of thiopurines
• Thiopurines -6-mercaptopurine, 6-thioguanine, and azathioprine -
treatment of leukemia , SLE, organ transplants.
• serious side effects, such as leukopenia and severe liver damage.
• Azathioprine - 10% to 15% of patients and it is possible to predict
those patients susceptible to side effects
21. e) Other Genetic polymorphisms in drug
metabolism :
• HLA B – a particular HLA allele (HLA-B*5701) and hypersensitivity
reactions to abacavir
• HLA-B*1502 screening is successful in patients who are prescribed
carbamazepine, particularly in Asians - carbamazepine-induced
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
22. f) COVID-19 and Pharmacogenomics
• Drug-gene variant pairs that may alter the therapeutic outcomes in COVID-
19 patients –
• CQ/HCQ (CYP2C8, CYP2D6, ACE2, and HO-1)
• azithromycin (ABCB1)
• LPV/r (SLCO1B1, ABCB1, ABCC2 and CYP3A)
• NVP (ABCC10)
• oseltamivir (CES1 and ABCB1)
• Remdesivir (CYP2C8, CYP2D6, CYP3A4, and OATP1B1)
• anakinra (IL-1a)
• TCZ (IL6R and FCGR3A)
23. g) CCR532 homozygosity and HIV therapy
• C-C chemokine receptor type 5, also known as CCR5 or CD195, is
a protein on the surface of WBCs
• involved in the Immune system as it acts as a receptor for chemokines
• In humans, the CCR5 gene that encodes the CCR5 protein
is chromosome 3p.
• Certain populations have inherited the Delta 32 mutation, resulting in
the genetic deletion of a portion of the CCR5 gene.
• Homozygous carriers of this mutation are resistant to M-tropic of
HIV1.
25. Management of APML and ATRA
• The management and outcome of acute promyelocytic leukemia
(APL) has been revolutionized by the introduction of all-trans retinoic
acid (ATRA; tretinoin) and arsenic trioxide (ATO)
• ATRA-sensitive variants - should include this agent in combination
with anthracycline-based chemotherapy
• ATRA-resistant variants - management should consist of AML-like
approaches
26.
27. •Angelina Jolie Effect –
• testing for BRCA mutation based on
family history of Breast Cancer found
87% risk of developing cancer.
• Bilateral Mastectomy lowered the risk to
<5% - 2013
28. Guidelines
• PharmGKB – Genotype and phenotype data related to drug response
• curates knowledge about the impact of genetic variation on drug
response for clinicians and researchers.
• Clinical Pharmacogenetics Implementation Consortium (CPIC) of
National Institutes of Health’s Pharmacogenomics Research Network
guidelines are designed to help clinicians understand HOW available
genetic test results should be used to optimize drug therapy
• Goals of the CPIC and the PharmGKB is to provide peer-reviewed,
updated, evidence-based, freely accessible guidelines for gene/drug
pairs. These guidelines will facilitate the translation of
pharmacogenomic knowledge from bench to bedside.
29. Regulatory Guidance
• FDA: Guidance: Guidance for Industry- Pharmacogenomic Data
Submissions
• EMEA- European Medical Agency
30. Barriers in progress
• Complexity of finding gene variations that affect drug response
• Limited drug alternatives
• Disincentives for drug companies to make multiple
pharmacogenomics products
• Expensive – No Insurance in Indian Scenario
• Access to genetic tests may be limited at some places
• Discrimination
31. ETHICAL CONCERNS
• Practical application at present in routine patient care is limited due
to pre requirement of multiple drug specific genotyping screening
which involves huge cost.
• May lead to ‘Discrimation’ in medical therapy provided to a patient –
treatment may be biased
• Discrimination on basis of ethnic and racial factors
32. • Rare genotypes (orphan genotypes)- deprived of health care – may
not enjoy insurance cover
• Pharmaceutical companies – will not be willing to invest in developing
drugs for groups with less common genotype – creation of
“therapeutic orphans”
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 mainstream of the healthcare
system.
• High cost and ethical concerns for privacy – major challenges.
• Constructive efforts from scientists, clinicians, ethicists and health
care managers can bring change in the lives of patients.
34. 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 mainstream of the healthcare
system.
• High cost and ethical concerns for privacy – major challenges.
• Constructive efforts from scientists, clinicians, ethicists and health
care managers can bring change in the lives of patients.
Notas do Editor
Kinetic – interaction of drug with
Dyanamic – interaction of drug with
