Transcript Problems with Rx Drugs

PHARMACOGENOMICS
By
V.VYTHESHWARAN
Problems with Rx Drugs
• We are all different…
• Most of us are treated in the same way
• Trial and error
Implications
• Time: Trips to and from doctor
• Money: Thousands spent on ineffective
medications
• Death/sickness: 2.2 million serious cases
and over 100,000 deaths.
PURINE ANALOGUES
• 6-mercaptopurine, 6-thioguanine,
azathioprine
• Used to treat lymphoblastic leukemia,
autoimmune disease, inflammatory bowel
disease and after transplant.
• Interfere with nucleic acid synthesis
• Therapeutic index limited by
myelosuppression
Metabolism of 6-Mercaptopurine
•Levels of Thiopurine smethyl transferase
(TPMT) can drastically
affect levels of
thioguanines
•More TPMT = less
thioguanines.
•Associated with risk of
severe marrow toxicity
•Shows considerable
variability in population
Variations in TPMT Genes
6-MP and TPMT Story Summary
• Clinical variability (toxicity).
• Cellular variability (TPMT activity,
thioguanine nucleotides concentrations).
• Genetic variability (genome variations in
TPMT gene)
How can we support this type of
discovery using informatics?
AN ANSWER????
• Pharmacogenomics: The study of how an
individuals genetic inheritance affects the body’s
response to drugs.
DEFINITION
Pharmacogenomics refers to the identification
and elucidation of genetic variations that will
impact the efficacy of drugs or offer different
targets.
Rather than being a radically new approach to
medicine, pharmacogenomics essentially
applies concepts about variations in drug
metabolism to the rest of genome.
Pharmacogenomics refers to the application of
tools from the functional genomics toolbox to
the discipline of pharmacogenetics.
BACKGROUND
• Fundamental to pharmacogenomics is the identification
and mapping of the most common form of genetic
variation - known as single nucleotide polymorphisms
(SNPs).
• SNPs occur on average every 1000 nucleotides. Due to
their relatively high density (compared with other forms
of genetic variation), SNPs can serve as useful markers
to navigate through the genome, whether one is trying to
locate disease-linked genes or to determine the risk of
developing a disease.
• Of the estimated total of 30 million SNPs in the entire
genome, a few hundred thousand are thought to occur
within these regions and of these perhaps only a few
thousand account for disease outcomes.
HISTORY
• The genetic contribution to drug metabolism was
originally defined using variations in drug levels or
responses of individuals and families. This was
suggested on a theoretical basis by Motulsky in
1957.
• The word "pharmacogenetics" was coined
approximately forty years ago by Vogel in 1959.
• Kalow wrote the first text book on this subject in
1962 .
• The field of pharmacogenetics was further stimulated
in the late 1970s when Vesell et al. demonstrated
that identical twins were more similar than fraternal
twins in regard to the plasma half-lives of
therapeutically used drugs.
PROSPECTS
• Pharmaceutical development and
therapeutic strategies in the coming years.
• Safer, more effective drugs.
• Better diagnostics, and improved clinical
trials, it may even lead to an era of
"personalized medicine" where therapies
are tailored to the genetic makeup of
different populations.
THE NEED… AN ILLUSTRATION
• A drug called azathioprine, is used in autoimmune
disorders, and childhood leukemia is metabolized, by the
enzyme called TMPT. Less than 0.5 % of Caucasians
carry a gene variant on both chromosomes that produces
an inactive protein and so can not metabolize the drug.
When patients with that gene variant are treated with
azathioprine, its blood levels built up to toxic levels,
leading to acute bone marrow failure. This happened to a
boy who was started on the drug and had to be rushed to
the Mayo Clinic for a marrow transplant, which saved his
life.
• A pharmacogenomic genetic test has been
developed to identify patients with this deficiency
which permits the use of an alternative therapy.
OBTAINING THE DNA
•
•
•
•
Person’s DNA sequenced through micro array
techniques
Micro arrays- evolving technology to examine
patients for specific SNPs quickly and
affordably
One micro array screen 100,000 SNPs in a
few hours
As technology develops, SNP screening
commonplace
Anticipated benefits of
Pharmacogenomics
• 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.
Anticipated benefits of
pharmacogenomics
• More Powerful 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
Anticipated benefits of
pharmacogenomics
• Advent of better, Safer Drugs
Instead of the standard trial-and-error method
of matching patients with the right drugs, doctors
will be able to analyze a patient's genetic profile
and prescribe the best available drug therapy
from the beginning. Not only will this take the
guesswork out of finding the right drug, it will
speed recovery time and increase safety as the
likelihood of adverse reactions is eliminated.
Anticipated benefits of
pharmacogenomics
• Advanced Screening for Disease
Knowing one's genetic code will allow a person
to make adequate lifestyle and environmental
changes at an early age so as to avoid or lessen
the severity of a genetic disease. Likewise,
advance knowledge of a particular disease
susceptibility will allow careful monitoring, and
treatments can be introduced at the most
appropriate stage to maximize their therapy.
Anticipated benefits of
pharmacogenomics
•
Improvements in the Drug Discovery and Approval
Process
– Discover potential therapies more easily using genome
targets.
– Previously failed drug candidates may be revived as they
are matched with the niche population they serve.
– Drug approval process – facilitated as trials are targeted
for specific genetic population groups --providing greater
degrees of success.
– Cost and risk of clinical trials will be reduced by targeting
only those persons capable of responding to a drug.
– As reported in the April 2001 issue of Pharmaceutical
Executive, "By 2010, pharmacogenomics is expected
to cut the cost of R&D by $33 million per product!!!”
Anticipated benefits of
pharmacogenomics
• Decrease in the Overall Cost of Health Care
– Number of adverse drug reactions.
– Number of failed drug trials, & the time it takes to get
a drug approved.
– Time period for which the patients are on medication.
– Number of medications patients must take to find an
effective therapy.
– Effects of a disease on the body (through early
detection).
– Increase in the range of possible drug targets.
THE NEEDS
• Softwares
• Pharmacogenomic tests
• New drugs based on pharmacogenomic
information
• Secure genotype banks
• Web- based clinical trials
THE BIG ?
• Can these studies actually be done for enough
diseases?
• Will enough diseases have a stronger genetic
than environmental component?
• Will SNPs be generally useful to find genetic
associations?
Risk of pharmacogenomics
Issues Raised by Ethics
Committees
•
•
•
•
•
•
•
Patient confidentiality/data privacy
Specify genes
Scope of sample use for future research
Length of storage period
Disclosure of individual results to patients
Limited sample withdrawal period
Samples cannot be used for commercial
purpose
• Sample ownership
• Investigator role in access/use of samples/data
”CONSUMER GENOMICS"
• Major pharmaceutical companies now
routinely study genetic effects on
drug metabolism and response as
part of drug discovery and
development.
• Genetic variation has been shown to
affect the action of many of the most
important drugs in the pharmacopia.
• A new field of "consumer genomics"
has been spawned to bring these
discoveries directly to the public.
Ethical, Legal and Social
Implications
• Fairness in the use of genetic information by
insurers, employers, courts, schools, adoption agencies,
and the military, among others.
– Who should have access to personal genetic
information, and how will it be used?
• Privacy and confidentiality of genetic information.
– Who owns and controls genetic information?
• Psychological impact and stigmatization due to an
individual's genetic differences.
– How does personal genetic information affect an
individual and society's perceptions of that individual?
Ethical, Legal and Social
Implications
• Reproductive issues including adequate
informed consent for complex and potentially
controversial procedures, use of genetic
information in reproductive decision making, and
reproductive rights.
– Do healthcare personnel properly counsel
parents about the risks and limitations of
genetic technology? How reliable and useful
is fetal genetic testing?
Ethical, Legal and Social
Implications
• Uncertainties associated with gene tests for
susceptibilities and complex conditions (e.g.,
heart disease) linked to multiple genes and
gene-environment interactions.
– Should testing be performed when no
treatment is available? Should parents have
the right to have their minor children tested for
adult-onset diseases? Are genetic tests
reliable and interpretable by the medical
community?
Ethical, Legal and Social
Implications
• Conceptual and philosophical implications
regarding human responsibility, free will vs
genetic determinism, and concepts of health and
disease.
– Do people's genes make them behave in a
particular way? Can people always control
their behavior? What is considered
acceptable diversity
Ethical, Legal and Social
Implications
• Safety and environmental issues concerning
genetically altered foods and microbes
• Commercialization of products including
property rights (patents, copyrights, and trade
secrets) and accessibility of data and materials
– Who owns genes and other pieces of DNA?
Ethical, Legal and Social
Implications
THE FUTURE????
THANK YOU