2. Part I ( basic concepts )
What is pharmacogenomics
Difference between the pharmacogenetics and pharmacogenomics.
What is psychopharmacogenomics
Historical aspects of pharmacogenomics
What are SNPs
Concept of CYP enzymes and genetics
Part II ( neuropsychopharmacogenomics)
Psychopharmacogenomics in relation to antideparessants ,
atipsyachotics and mood stabilizers.
Psychopharmacogenomics in relation with the drug development in
psychiatry
7. Pharmacogenetics : study of the effect of
single gene on the response of various
drugs
Pharmacogenomics : study of the effect of
multiple genes on the response of various
drugs
8. Psychopharmacogenomics :
Study of the effects of variations in multiple
genes on the response of drugs used in
psychiatry and the psychiatric disorders.
10. Variability in Drug Response
Disease Drug Class Rate of Poor response
Asthma Beta-agonists 40-75%
Hypertension Various 30%
Solid Cancers Various 70%
Depression SSRIs, tricyclics 20-40%
Diabetes Sulfonylureas, others 50%
Arthritis NSAIDs, COX-2 inhibitors 30-60%
Schizophrenia Various 25-75%
11. ( lieberman et al N Engl J Med 2005)
Clinical antipsychotic trials of intervention
effectiveness (CATIE) : 18 months
74% discontinued : lack of efficacy or tolerability.
13. Scenario
All patients with same diagnosis
1 Non-responders
and toxic
responders
2
Responders and patients
not predisposed to toxicity
14. This can be improved by
Giving the Right Drug
At Right Dose
To the Right Patient
At the Right Time
Patient specific selection of medication and their dosage
16. Pharmacogenomics holds the promise that drugs might one day be
tailor-made for individuals and adapted to each person's own
genetic makeup.
Environment, diet, age, lifestyle, and state of health all can influence
a person's response to medicines, but understanding an
individual's genetic makeup is thought to be the key to creating
personalized drugs with greater efficacy and safety.
20. Important Facts
Human genome = 22 chromosome pairs and 1
pair of sex chromosomes
Functional unit of the genome = gene
2% of genes code for proteins, remainder is
structural for DNA
Entire genome = 3 billion DNA pairs, with
~30,000 protein coding genes
21.
22. Allele
An allele is one member of a pair that makes up
a gene
2 same alleles are homozygous (one allele on
each part a pair of chromosomes)
2 different alleles are heterozygous
23.
24. • DNA sequence of all human beings is
99.9% identical
• Our DNAs differ by 0.1%. •
Does it make a difference ?
YES !
0.1% difference translates into 3 million
separate “spelling” differences in a
genome of 3 billion bases
25. Genetic Polymorphism?
A genetic polymorphism is any
mutant or variant gene that
occurs with a frequency of
more than 1% in the normal
population
Denoted by : *
26. POLYMORPHISM TYPES
SNP INSERTIONS DELETIONS
• Missense • Missense • Missense
• Nonsense • Nonsense • Nonsense
• Frameshift • Frameshift • Frameshift
Go to
39. Impact of CYP2C9*2 genetic polymorphism on enzymatic activity
Nucleotide # 430 C G T
CYP2C9*1
Exon 3
Amino acid #144 Arg Normal enzymatic activity
Nucleotide # 430 T G T
CYP2C9*2
Exon 3
9
Amino acid #144 Cys Reduced enzymatic activity
40. What do the CYPs do?
Drug metabolism throughout the
body
Activate drugs
Detoxify substances and activate
non-toxic substances into toxic
substances
48. Why diazepam metabolism is slower in Asians
compared to Caucasians?
Because Asians have high frequency of mutant alleles CYP2C19
Genotype Allele Diazepam t1/2
caucasians CYP2C19 *1/*1 20 hours
FM
Asians CYP2C19 *2/*2 84 hours
PM
50. Function of P-gp
The human MDR1 encodes a
membrane P-glycoprotein that
mediates ATP-dependent efflux.
P-gp resides in the plasma membrane
and functions as an efflux transporter of
a wide variety of natural compounds
and dugs
52. Receptor Sensitivity/Effect
Subjects with Gly 389 have reduced
β1 receptor gene
Arg389Gly sensitivity to beta-blockers
Ser49Gly Subjects with Gly 49 have increased
sensitivity to beta-blockers
56. This girl may develop side effects to
Warfarin Glibenclamide
Acenocoumarol Tolbutamide
Losartan Ibuprofen
Irbesartan Flurbiprofen
Glipizde Diclofenac
All metabolized by CYP2C9 enzyme
57. CYP2D6 Polymorphisms and
Psychiatric Drug Response
Increased rate of adverse effects in poor
metabolizers due to increased plasma
concentrations of drug:
Fluoxetine (Prozac®) death in child attributed to
CYP2D6 poor metabolizer genotype
Side effects of antipsychotic drugs occur more
frequently in CYP2D6 poor metabolizers
CYP2D6 poor metabolizers with severe mental illness
had more adverse drug reactions, increased cost of
care, and longer hospital stays
64. • An investigative drug showed NO
statistically significant effect when given
to 400 Alzheimer’s patients,
• A clinically significant response was
elicited when patients were stratified
according to ApoE subtype
(Richard et al., 1997).
72. Phase II/III studies
Identify genetically-defined groups
with more pronounced or rapidly
progressing disease
Exclude/include at-risk individuals
Stratify studies based on genotypes
Clinical response
Risk of adverse events
Where appropriate, develop drugs for
specific groups
73. FDA and Pharmacogenomics
FDA published: “Draft Guidance for Industry:
Pharmacogenomic Data Submission” in 2003.
(currently under revision)
Set criteria for Voluntary Genomic Data
Submission (VGDS)
(http://www.fda.gov/cder/guidance/5900dft.pdf)
74. What are the anticipated benefits of
Pharmacogenomics?
75. Individualized Medicines
Pharmaceutical companies will be able to
create drugs based on the proteins,
enzymes, and RNA molecules associated
with genes and diseases.
This will facilitate drug discovery and allow
drug makers to produce a therapy more
targeted to specific diseases. This accuracy
not only will maximize therapeutic effects
but also decrease damage to nearby healthy
cells.
76. Cost Effectiveness ?
• Phase III trial - CNS product -4500 patients- Cost per patients
$ 8000 - $ 12,000
• Eliminate 10% (Approx 450 subjects) of trial population (Non-responders) Using
Pharmacogenomic
Save $ 3,60,000 - $5,40,000.
(Murphy , Pharmacogenetics, 2000; 10:1-7)
77. Some ethical Issues
Could the development of medicines for
specific groups of the population exclude
others?
Will the development of unprofitable, but
desirable, medicines be neglected?
Who will have access to genetic information
and databases?
78. Research Issues
Translating
• Narrower target population could exclude those
who might also benefit from therapies
• Evaluating therapies in smaller, targeted trials
might miss critical, albeit rare, adverse drug events
79. Social Issues
Health Horoscope
Will I develop this
disease ten years from
now?
• Can I indulge in
unhealthy habits (e.g.,
smoking, junk
food, not exercising,
etc.) if I don’t have a
particular disease
susceptibility?
80.
81. Patient requires Treatment
Examination by the Physician
Genomic testing Traditional
investigations
EXPERT SYSTEM
Decision making by Physician, assisted by an
Expert System (interactive interpretation)
Prescribes individualized drug treatment
86. The Next Diagnostic Chips?
Additional diagnostics are needed:
General: CYP2C9; CYP3A5; CYP2B6;
MDR-1; UDP Glucuronosyltransferases
(UGTs);
N-acetyltransferases (NATs)
Oncology: thiopurine methyltransferase
(TMPT);
Thymidilate synthase; dihydropyrimidine
87. Personalized Medicine:
“when?”
SMART CARD In your wallet by 2025?
Praveen khairkar
97236407611
GENOME Or maybe by 2050?
(Confidential)
Opinion: This sort of card would initially (~2025?) include mostly
information related to drug metabolizing enzymes
Around ~2050 it might include an entire individual genome
(or at least, few millions SNPs..)
88. Science or Science Fiction ?
Unrealistic projections for 2025:
Most medicines will be prescribed
according to patient genotyping
Genomics would allow full insight into
the biological basis of complex human
diseases
89. PGx: Science and Science Fiction
Realistic projections for 2025
Genotyping would allow far smaller rates
of adverse reactions for most drugs
In several medical disciplines, genomics
would allow far better medical treatment
(oncology; psychiatry; neurology)
92. Part I
What is pharmacogenomics
Difference between the pharmacogenetics and pharmacogenomics.
What is psychopharmacogenomics
Historical aspects of pharmacogenomics
What are SNPs
Concept of CYP enzymes and genetics
Part II
Psychopharmacogenomics in relation to antideparessants ,
atipsyachotics and mood stabilizers.
Psycchopharmacogenomics in relation with the drug development
in psychiatry
93. Conceptual reality or awaiting dream ?
Definitely a conceptual reality
For grass root patients and practitioners
… there is still a long long way to go …to
fulfill the dream …
94. Acknowledgements
Dr. Praveen Khairkar
Dr. Sushil Verma
Dr. Aniket Shukla
Dr. Adithan
Google and Wikipedia
