(Philadelphia, PA) - Two studies published this
week from the University of Pennsylvania School of Medicine
point to the need for a more individual approach to medicine and
drug testing. The two papers, from the lab of Garret FitzGerald,
MD, Director of Penn’s Institute for Translational
Medicine and Therapeutics, together with Penn colleagues Tilo
Grosser MD, Research Assistant Professor of Pharmacology,
and Susanne Fries MD, Research Associate in Pharmacology,
highlight clinical studies involving COX-2 inhibitors as an example.
The first study, published in the Journal of Clinical Investigation,
summarizes comprehensively the basic and clinical evidence that
explains how drugs like rofecoxib (VIOXX), celecoxib (CELEBREX),
and valdecoxib (BEXTRA) confer a small, but absolute, risk of heart
attack and stroke. The size of this risk is likely to be conditioned
by the underlying risk in a given patient of thrombosis and heart
disease; the dose and duration of action of a drug; and the duration
of dosing and concurrent therapies, such as low-dose aspirin.
The authors indicate how the clinical information from placebo-controlled
trials of the COX-2 inhibitors is congruent, both in outcome and
in how the information became manifest, with what would be expected
from how the drugs work pharmacologically to block the COX-2 enzyme.
The authors synthesize information from an understanding of drug
mechanisms and epidemiology to predict how traditional NSAIDs-drugs
like diclofenac, ibuprofen, and naproxen-may differ with respect
to cardiovascular risk. Finally, they synthesize this information
to provide a rational basis for treating patients with varied risk
profiles as physicians await further information from ongoing trials.
Lessons are drawn from the experience of the COX-2 inhibitors-particularly
the need to develop a more interdisciplinary approach to drug development
and monitoring of drug safety and how an emphasis on individualizing
benefit and risk can be used to refine the design of clinical trials.
The second paper, published in Gastroenterology, builds
on the theme of individualized therapy, demonstrating marked variation
in individual response to COX-2 inhibitors, as measured by plasma
drug levels and the degree of COX-2 inhibition within an individual.
The researchers found that a marked degree of variability in individuals
dosed with either rofecoxib or celecoxib, even when they studied
apparently healthy, relatively young individuals in a carefully
controlled environment. This rigorous study suggests that up to
a third of the variability may reflect an individual's genetics.
Examples are given of variants in genes that affect either drug
metabolism or the COX enzymes themselves.
The study was conducted on 50 healthy volunteers between the ages
of 21 and 43 years old who received a single dose of placebo, celecoxib
and rofecoxib in random order. This was done to allow researchers
to compare directly the responses to the drugs within the same subjects.
Five of the patients went thru the entire protocol 5 times to assess
variability within individuals. “A surprise of the study was
that factors in our environment result in varied response of the
same individual to the same dose of a drug, even when we try to
standardize as many variables as we can think of,” says Grosser.
Approximately 30 percent of the variability found in patients was
attributable to differences between individuals, suggesting the
contribution of genetics to a variety of biomarkers of drug response.
Fries, the first author of the Gastroenterology study,
explains that this work provides the impetus to develop a science-based
approach to risk management. “Exploitation of variability
in response can lead to tests which identify patients most likely
to benefit or suffer from drugs,” she says. “Our study
provides a starting point for the development of diagnostics that
will let us conserve benefit while managing the risk of COX-2 inhibitors.”
Such work heralds the rapidly emerging field of individualized medicine,
says FitzGerald. “This can guide both the design of future
clinical trials and the use of these drugs in practice.”
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