Take two aspirin . . ." starts the punch line of many a medical joke. It's never "Take one aspirin" or "Take three aspirin." That's because dosing recommendations, whether for good old aspirin or for sophisticated anticancer drugs, are based on the response of an average patient. Even the standard testing and approval process that the Food and Drug Administration (FDA) puts drugs through has historically defined the response of an average patient to a particular dose of a particular drug.

Yet not all patients respond to the same drug in the same way. A drug shown to help most patients might offer no benefit to some-- and could even pose grave danger to a few patients who, because of their genetic constitution, fall outside the normal bell curve of the response.

But with the recent advent of quick, cost-effective assays for specific genetic variations, that uncertainty may soon vanish. For example, in August 2005 the FDA approved a screening test for genetic variations in an enzyme called UGT1A1, which affects patients' response to a drug for colorectal cancer. A month later, the Molecular Pathology Laboratory at DMS became the first facility in the U.S. to offer UGT1A1 screening.

The FDA has only recently started recommending that genetic makeup be a consideration in dosing regimens. In the case of UGT1A1, the packaging information for Camptosar, used to treat

colorectal cancer, was modified in June 2005 to indicate that patients who are homozygous for a specific allele of the gene that produces UGT1A1 (whose full name is UDP-glucuronosyl transferase 1A1) should receive a lower dose of the drug.

This recommendation was based on the observation that UGT1A1, an enzyme involved in breaking down the active metabolite of Camptosar, shows reduced activity in about 10% of the population, those who have a specific form of the gene for UGT1A1.

When such patients receive a standard dose of Camptosar, the metabolite accumulates in their plasma, potentially exposing them to toxic levels of the drug. By doing a genetic test prior to treatment, physicians can identify patients at risk of drug toxicity and treat them with a lower dose of the drug.

Assay: The company that developed the UGT1A1 assay offered Dartmouth a chance to pioneer its use based on earlier successful collaborations, says Dr. Gregory Tsongalis, director of DHMC's Molecular Pathology Laboratory. About 20 to 30 assays were performed in the first six weeks, and Tsongalis expects the numbers to grow. "Many inquiries are coming through the patients themselves," he notes. The program fits in well with the overall development of pharmacogenetics in the Department of Pathology. Tsongalis says the department has several other genetic screening tests under

development; he hopes that the UGT1A1 assay will be only the first of an array of screenings. Meanwhile, the FDA is rethinking how variability in drug response should be factored into the approval process for new drugs. The FDA would like to see genetic screening used to define more precisely those who will receive maximal effect from, or be endangered by, a particular drug. Yet not all of the parties involved in the approval process are happy with this approach.

Detect: For example, Aczone, a new drug for acne, received FDA approval in July 2005. As a condition of its approval, the FDA stipulated that potential patients be screened to detect if they have a specific enzyme deficiency that could predispose them to developing hemolytic anemia while they're taking the drug. But the manufacturers of Aczone view genetic testing requirements as an attempt to limit the population of patients who can be prescribed their product and challenged the FDA decision. They are arguing that the at-risk population is very small and that anemia was not seen during preapproval trials.

Yet Tsongalis and others feel that the benefit to patients outweighs such concerns. Furthermore, he suggests that genetic screening might even work to drug-makers' benefit. "Right now certain patient populations that could benefit from a drug are excluded based on the population response," he says. "Genetic testing could open up new markets for drugs that would not have been approved otherwise."

Joseph Melton, Ph.D.