FDA Releases List of Genomic Biomarkers Predictive of Drug Interactions

Jacquelyn K. Beals, PhD

August 01, 2008

August 1, 2008 — The US Food and Drug Administration (FDA), as part of its Critical Path Initiative, has compiled a table of genomic biomarkers with established roles in drug response. The initiative, launched in 2004, encompasses the goal of identifying "patients likely to benefit from a treatment and patients more likely to respond adversely to a product," according to FDA's Office of Management, Budget Formulation and Presentation.

At present, about 10% of drugs approved by the FDA include pharmacogenomic information on their labels. Using genomic profiles, physicians can identify patients who will (or will not) respond to a given drug, those patients who metabolize drugs faster or slower than average, and individuals at risk for drug toxicity. Using clinically proven biomarkers in drug therapy decisions is an important step on the road to personalized medicine.

The table compiled by the FDA lists validated genomic biomarkers, along with links to pharmacogenetic information. For each biomarker, the table indicates whether pharmacogenomic testing is "required," "recommended," or for "information only" within the context of a specific drug.

Maraviroc (Selzentry, Pfizer) is one drug in the FDA table for which testing is required. As a CCR5 coreceptor antagonist used in patients with only CCR5-tropic HIV-1 detectable infection, the drug "blocks a specific receptor called CCR5 that CCR5-tropic HIV-1 uses to enter CD4 or T-cells," states the table entry. HIV uses CCR5 or another protein, CXCR4, as receptors to enter cells. Because Selzentry is not effective against CXCR4-using virus, a test is required to determine whether the HIV infection is CCR5-tropic HIV-1, and whether the drug should be prescribed.

Another drug for which testing is required is trastuzumab (Herceptin, Genentech). Herceptin is a monoclonal antibody that binds strongly and selectively to the extracellular portion of HER2 (the human epidermal growth factor receptor 2 protein). HER2 is overexpressed in 25% to 30% of primary breast cancers, and studies have shown that Herceptin's cytotoxicity is preferential against cells that overexpress HER2 compared with other cancer cells. The table entry advises: "Detection of HER2 protein over-expression is necessary for selection of patients appropriate for Herceptin therapy."

The drugs in the preceding examples would have little, or very reduced, efficacy in patients who are not infected with CCR5-tropic HIV-1 or who do not overexpress HER2. In contrast, testing may be recommended to avoid the risk of excessive drug sensitivity or toxicity. Two drugs in this category are warfarin and rasburicase.

In the case of warfarin, an anticoagulant, studies have shown that patients with specific variants of CYP2C9 (cytochrome P450) have a greater risk of bleeding. For allele CYP2C9*2, patients with at least 1 copy should receive 17% less warfarin per day than patients homozygous for the CYP2C9*1 allele. Patients with a copy of allele CYP2C9*3 should receive 37% less warfarin than the CYP2C9*1 homozygotes to avoid the risk of bleeding.

Rasburicase is used to treat patients with hematologic malignancies. Pretesting is recommended because patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop "severe hemolysis" when taking this drug, the FDA table notes. G6PD deficiency is more common in patients with Mediterranean or African heritage, and screening is strongly recommended for this population.

The FDA table is updated every few months as new drugs and genomic information become available; the version currently online was created September 15, 2006, and was most recently updated July 31, 2008. An FDA Consumer Health Information article, "How FDA Advances Personalized Medicine," points out the challenges of incorporating pharmacogenomic testing into drug selection.

"Using a pharmacogenomic test to determine who will respond to a treatment or who should not get a treatment may narrow the market for certain drugs," the article acknowledges. It may take years to identify all the genetic variations, and patients' responses may depend not on a single gene but, rather, on multiple genes, as well as their interactions. Nevertheless, in its Critical Path Initiative, the FDA is working "to bring balance to an evolving science in a way that does not inhibit its growth."

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