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What is pharmacogenomics?
Pharmacogenomics is the study of how an individual's genetic inheritance affects
the body's response to drugs. The term comes from the words pharmacology and
genomics and is thus the intersection of pharmaceuticals and genetics.
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.
Pharmacogenomics combines traditional pharmaceutical sciences such as biochemistry
with annotated knowledge of genes, proteins, and single nucleotide polymorphisms.
What are the 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.
- Better, Safer Drugs the First Time
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.
Pharmacogenomics has the potential to dramatically reduce the the estimated
100,000 deaths and 2 million hospitalizations that occur each year in the
United States as the result of adverse drug response (1).
- More Accurate Methods of Determining Appropriate Drug Dosages
Current methods of basing dosages on weight and age will be replaced with
dosages based on a person's genetics --how well the body processes the medicine
and the time it takes to metabolize it. This will maximize the therapy's value
and decrease the likelihood of overdose.
- 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.
- Better Vaccines
Vaccines made of genetic material, either DNA or RNA, promise all the benefits
of existing vaccines without all the risks. They will activate the immune
system but will be unable to cause infections. They will be inexpensive, stable,
easy to store, and capable of being engineered to carry several strains of
a pathogen at once.
- Improvements in the Drug Discovery and Approval Process
Pharmaceutical companies will be able to 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. The drug approval
process should be facilitated as trials are targeted for specific genetic
population groups --providing greater degrees of success. The cost and risk
of clinical trials will be reduced by targeting only those persons capable
of responding to a drug.
- Decrease in the Overall Cost of Health Care
Decreases in the number of adverse drug reactions, the number of failed drug
trials, the time it takes to get a drug approved, the length of time patients
are on medication, the number of medications patients must take to find an
effective therapy, the effects of a disease on the body (through early detection),
and an increase in the range of possible drug targets will promote a net decrease
in the cost of health care.
Is pharmacogenomics in use today?
To a limited degree. The cytochrome P450 (CYP) family of liver enzymes is responsible
for breaking down more than 30 different classes of drugs. DNA variations in
genes that code for these enzymes can influence their ability to metabolize
certain drugs. Less active or inactive forms of CYP enzymes that are unable
to break down and efficiently eliminate drugs from the body can cause drug overdose
in patients. Today, clinical trials researchers use genetic tests for variations
in cytochrome P450 genes to screen and monitor patients. In addition, many pharmaceutical
companies screen their chemical compounds to see how well they are broken down
by variant forms of CYP enzymes (2).
Another enzyme called TPMT (thiopurine methyltransferase) plays an important
role in the chemotherapy treatment of a common childhood leukemia by breaking
down a class of therapeutic compounds called thiopurines. A small percentage
of Caucasians have genetic variants that prevent them from producing an active
form of this protein. As a result, thiopurines elevate to toxic levels in the
patient because the inactive form of TMPT is unable to break down the drug.
Today, doctors can use a genetic test to screen patients for this deficiency,
and the TMPT activity is monitored to determine appropriate thiopurine dosage
1. J. Lazarou, B. H. Pomeranz, and P.
N. Corey. Incidence of adverse drug reactions in hospitalized patients:
a meta-analysis of prospective studies. JAMA. Apr 15, 1998. 279(15):1200-5.
2. J. Hodgson, and A. Marshall. Pharmacogenomics:
will the regulators approve? Nature Biotechnolgy. 16:
3. S. Pistoi. Facing your genetic destiny, part
II. Scientific American. February 25, 2002.
What are some of the barriers to pharmacogenomics
Pharmacogenomics is a developing research field that is still in its infancy.
Several of the following barriers will have to be overcome before many pharmacogenomics
benefits can be realized.
- Complexity of finding gene variations that affect drug response
- Single nucleotide polymorphisms (SNPs) are DNA sequence variations
that occur when a single nucleotide (A,T,C,or G) in the genome sequence
is altered. SNPs occur every 100 to 300 bases along the 3-billion-base
human genome, therefore millions of SNPs must be identified and analyzed
to determine their involvement (if any) in drug response. Further complicating
the process is our limited knowledge of which genes are involved with
each drug response. Since many genes are likely to influence responses,
obtaining the big picture on the impact of gene variations is highly
time-consuming and complicated.
- Limited drug alternatives - Only one or two approved
drugs may be available for treatment of a particular condition. If patients
have gene variations that prevent them using these drugs, they may be
left without any alternatives for treatment.
- 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.
Since it costs hundreds of millions of dollars to bring a drug to market,
will these companies be willing to develop alternative drugs that serve
only a small portion of the population?
- Educating healthcare providers - Introducing multiple
pharmacogenomic products to treat the same condition for different population
subsets undoubtedly will complicate the process of prescribing and dispensing
drugs. Physicians must execute an extra diagnostic step to determine
which drug is best suited to each patient. To interpret the diagnostic
accurately and recommend the best course of treatment for each patient,
all prescribing physicians, regardless of specialty, will need a better
understanding of genetics.
- Encyclopedia Dictionary of Genetics, Genomics, and Proteomics (2nd
Edition) by George P. Redei. 1024 pp., 2003.
- Pharmacogenomics: Social, Ethical, and Clinical Dimensions, edited
by Mark Rothstein. 384 pp., 2003.
- Pharmacogenomics: The Search for Individualized Therapies, edited
by Julio Licinio and Ma-Li Wong. 600 pp., 2002.