Prescribing With Precision
New research at IUSM zeroes in on an individual’s genetic
makeup and how it affects the body’s response to certain drugs.
The promise: a new era of more effective medications. Whenever we
take medicine, our bodies go to work on it. Often the drug must
first be broken down and converted to a useful form called a metabolite.
Then it must be delivered to places in the body where it’s
needed, and eventually it must be eliminated. Thanks to our individual
genetic makeup, each of us does all this a little bit differently.
Take codeine, for example, the world’s most commonly prescribed
opiate painkiller. Once codeine has entered the body, it is broken
down by an enzyme – CYP 2D6 – and converted into morphine.
The morphine brings the pain relief.
But not always. About seven of every one hundred people have a
gene that makes a form of CYP 2D6 that won’t convert codeine
to morphine. These individuals don’t get pain relief, just
nausea.
The fact that individuals respond differently to drugs is no secret.
For years, physicians and their frustrated patients have had to
work their way through alternatives before finding effective treatments
for such diseases as arthritis. Now, however, with the deciphering
of the human genome, comes the promise of an era in which tests
will help physicians tailor treatments to our genetic makeup. Pharmacogenetics
is the term coined to mean how genetic inheritance affects an individual’s
response to drugs.
Over the past year, Indiana University School of Medicine has moved
into the advance guard of pharmacogenetics research, thanks to the
arrival of new faculty and the impetus provided by the Indiana Genomics
Initiative.
Leading the charge is Professor David Flockhart, MD, PhD, who arrived
at IUSM in the summer of 2001 after being named chief of the Division
of Clinical Pharmacology in the Department of Medicine. He brought
with him seven researchers, swiftly making IU a site in the national
Pharmacogenetics Research Network organized by the National Institute
of General Medical Sciences, part of the National Institutes of
Health.
“The actual science behind pharmacogenetics is more compelling
than it’s ever been,” says Dr. Flockhart. The goal,
he says, is personalized medicine – or precision prescriptions.
The Pediatric Challenge
Pioneering the pharmacogenetics effort in pediatrics are Kathleen
A. Neville, MD, and Jamie L. Renbarger, MD. Both came to IUSM in
September from Baylor University, where they completed fellowships
in pediatric hematology/oncology. Drugs in general have not been
adequately studied in children, they say, and the details of how
genetics affects the activity of drugs in young patients are particularly
ripe for research. They believe the School of Medicine offers an
excellent opportunity to do that research and to use it clinically.
Dr. Renbarger initially will attempt to find genotypes that affect
how children respond to vincristine, a chemotherapy drug used to
treat a variety of pediatric cancers. Dr. Neville will conduct similar
studies in sickle cell disease, looking at the effect of genetic
factors on children’s responses to codeine used to treat the
pain of
sickle cell crises.
“We’re very committed to building something here in
pediatrics,” Dr. Renbarger says. “It’s exciting
and it’s fun and it’s interesting to think about, but
it’s also really challenging.”
Designer Drugs
How a child (or adult) responds to a drug isn’t controlled
by a single gene; for instance, there’s no “vincristine
response gene.” Rather there are genes that affect whether
and how fast a drug is metabolized, genes that play roles in transporting
drugs to the appropriate sites in the body, genes that determine
whether the cells there have the necessary receptors to latch on
to the drugs once they arrive, and more.
Gray Matter and Gray Areas
In psychiatry, Department Chair Christopher McDougle, MD, notes
that current psychiatric drugs are effective in up to seventy percent
of patients, depending on the drug and disease. But that still leaves
nearly a third of all patients who don’t benefit from a particular
drug. The goal, then, is a genetic test that would predict if and
how a patient will respond to a particular drug.
“Wouldn’t it be nice if we could do that?” he
muses. “I think eventually we will get there, but I wouldn’t
want to be overly optimistic.”
Even if identifying the appropriate genes to determine a patient’s
reaction to a psychiatric drug is easier than finding the genes
associated with the disease itself, it still will be a tough chore,
Dr. McDougle adds.
Dr. Flockhart notes that eventually there is likely to be a standard
set of 100 or 200 specific changes in genes that are relevant for
prescribing drugs.
“There would be a standard set that everyone would get. But
in order to get to that point we need to decide what that standard
set is,” he says.
While clinicians proceed to tackle such challenges, other scientists
will take on thorny social and ethical concerns. For instance, a
genetic test that helps a patient get the right form of hypertension
drug might also suggest that the patient is predisposed to heart
disease. So care will need to be taken that new knowledge brings
better diagnosis and treatment with protection of individual privacy
and without racial or ethnic stereotyping.
To address these needs, the School already is moving into the
study of pharmacogenetics and ethics and has awarded a fellowship
in pharmacogenomics, ethics and public policy, sponsored by the
Indiana University Center for Bioethics and the Division of Pharmacology.
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