Metabolomics and Personalized Medicine : Benefits

by Food and Drug Administration (FDA)

(Page 2 of 3)

What Are the Potential Benefits?

Metabolomics researchers believe the field has enormous potential to improve human health in a number of ways:

• To make safer drugs by predicting the potential for adverse effects (toxicity) earlier
• To target specific groups of people most likely to benefit from a drug, while excluding its use by those who may be harmed by it
• To speed the discovery and development of drugs
• To diagnose disease or predict the risk of disease
• To determine whether a treatment is working or not
• To monitor healthy people to detect early signs of disease.

The FDA approves drugs based on their safety and effectiveness in clinical trials. But sometimes, after a drug is on the market, it causes rare but bad reactions (adverse events) in some people that were not seen in clinical trials. One of these common adverse events is injury to the liver, but other organs such as the skin, heart, kidneys, and brain may be affected.

Liver injury brought on by a drug is the leading cause of acute liver failure in the United States and is the most frequent reason a new drug is removed from the market, says John Senior, M.D., associate director for science in the Office of Pharmacoepidemiology and Statistical Science within the FDA's Center for Drug Evaluation and Research (CDER). Part of the problem, says Senior, is that clinical trials are controlled studies of a specific group of patients who have been screened and who meet stringent criteria to be included in the study. Once approved, a drug is given to a much larger, more diverse population. "You find a problem that pops up after making the drug more available — problems you never had in controlled clinical trials."

Researchers within the NCTR and CDER are using metabolomics, integrated with proteomics and genomics, to try to find out what makes certain people especially susceptible to liver damage from a drug, while most patients are not harmed by it.

"By looking at metabolite pattern differences in urine and blood, we can find out in what measurable way people are different," says Senior. "The value is not only being able to understand the mechanisms by which injury is caused, but to be able to develop tests to detect individual metabolic differences in response to a drug and to predict who shouldn't take a particular drug."

"Early identification of susceptible people would avoid removing approved drugs from use because of rare but serious adverse effects," adds Senior. "If you knew who was at risk, you could safely give the drug to others who could benefit from it."

Other applications of metabolomics lie in the drug discovery and development process. To find new drugs to treat people, potential compounds are first tested on animals. Animals and humans may show consistent changes in metabolism in response to a disease or to the effects of drugs, says Beger. Although there are genetic differences between species, many metabolites are very similar, he says. For example, the fat, cholesterol, and glucose metabolites in a rat and in a human are the same, "so we can translate our results a lot easier between species."

"The technology shows tremendous impact early on in drug discovery," says Donald Robertson, Ph.D., a toxicologist and director of the Metabonomics Evaluation Group at Pfizer Global Research and Development in Ann Arbor, Mich. "The goal is to move the safety evaluation earlier into the discovery process." Using metabolomics, says Robertson, "we can show toxicity at an early stage in drug development and in a less invasive way, so fewer animals are needed for research."

"One of the big concerns is keeping drug development costs down early on, which is a benefit for everyone," adds Robertson. The Tufts Center for the Study of Drug Development reports that on average, a new drug costs $802 million to develop, with most of that cost going toward failed drugs. And, according to the Pharmaceutical Research and Manufacturers of America, of every 5,000 drugs screened, only five make it into testing in clinical trials. Only one of these five drugs eventually gets approved for marketing, yet all of them cost millions of dollars to develop.

Metabolomics can help weed out drugs that are unsafe early on, says Robertson. "The earlier they fail, the less expensive it is."

Knowing who might have a bad reaction to a drug would also help researchers design clinical trials better, says Senior. The trials could include only people most likely to benefit from the drug based on their metabolic profile, and could exclude those for whom the drug would be toxic or ineffective.

In addition to helping develop safer drugs more quickly and at less cost, scientists predict that metabolomics will lead to developing noninvasive screening tests for more diseases. Some individual metabolites are already being used as indicators, or biomarkers, of disease. For example, high levels of the metabolite cholesterol in the blood indicate an increased risk of heart disease, and high levels of the metabolite glucose in the urine signal a risk of diabetes.

When a person goes to a doctor, lab tests are done to check for a limited number of biomarkers, says Dragan. "With metabolomics, you could look at a broader range of potential problems — a whole lot more than just the half dozen things that we currently look at."

Researchers at the Imperial College of Science, Technology and Medicine in London were able to diagnose heart disease and its severity with metabolomics. They evaluated the metabolites in plasma to identify people whose major coronary arteries had narrowed, indicating a risk of heart disease. The scientists see their technique as a rapid, noninvasive screening test to diagnose blocked arteries, "allowing diagnosis to be made simply and cheaply on the basis of a single blood sample," writes lead researcher Joanne Brindle in the December 2002 issue of Nature Medicine. Such a test might replace the current standard test, angiography, an invasive procedure in which a catheter is inserted into the groin and threaded through the body up to the arteries.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.