A relatively simple technique, pioneered by a North Carolina physician, can distinguish between patients who can metabolize docetaxel(Drug information on docetaxel) (Taxotere) normally and those who need to receive lower doses for safety, according to a recent study. Researchers say the approach might work for other chemotherapeutic agents and perhaps other noncancer drug treatments as well.
Because of diet, genetics, and other factors, some people just metabolize drugs a lot more slowly, said Paul B. Watkins, MD, professor of medicine and director of the Verne S. Caviness General Clinical Research Center at the University of North Carolina at Chapel Hill School of Medicine. As a result, the recommended dose of many chemotherapies will predictably make about 10% of patients very ill, and 1% or 2% of patients may die as a direct result of the treatment. Conversely, patients whose livers rapidly clear a given chemotherapy may not get a dose strong enough to be effective against their cancer, he said.
A report on the new study appears in the April issue of Clinical Cancer Research. Besides Dr. Watkins, the study was authored by Drs. JoAnn Hirth, Myla Strawerman, Anne Schott, and Laurence Baker of the University of Michigan.
Carbon Dioxide Levels Give Clues
Investigators took blood samples from 21 cancer patients several times over 24 hours to determine how fast their livers cleared the drug docetaxel and compared those results with measurements of the patients breath. In the 20-minute breath test, which Dr. Watkins developed and patented, doctors gave patients a trace dose of the common antibiotic erythromycin(Drug information on erythromycin) and measured the amount of carbon dioxide they exhaled.
Higher concentrations of exhaled carbon dioxide meant that patients were metabolizing erythromycin more quickly, and lower concentrations meant they were metabolizing it more slowly, Dr. Watkins said. The liver uses the same enzyme system, or pathway, to clear docetaxel as it does to process erythromycin.
We didnt look at the data until the study was over, Dr. Watkins said. Among other things, we found that the two patients who got very ill and had to be hospitalized showed the lowest test results and the lowest levels of enzyme activity.
Test Shows Promise
In an accompanying editorial, Dr. Jerry M. Collins, director of the Laboratory of Clinical Pharmacology at the US Food and Drug Administration, said that the new assay, which builds on a tradition of using breath tests as indicators of liver function, has numerous promising advantages.
It is rapid, relatively noninvasive, requires only a single time point, and can be used prospectively before dosing, he said. Because of the narrow therapeutic range of anticancer drugs, lowering the likelihood of toxicity in patients at greatest risk is a useful contribution.
Dr. Watkins said that while it is not proven yet, other forms of chemotherapy likely employ the same pathway measured by his breath test. Even if they do not, comparable simple tests probably can be developed that will help protect patients treated with drugs metabolized via different enzymes.