CHICAGO (GenomeWeb News) – Despite mounting evidence that genetics can affect the way some individuals process drugs, identifying genetic variants associated with drug response is just the first step in a long road to implementing the information in the clinic, according to a speaker at the American Association for the Advancement of Science meeting in Chicago this weekend.
Speaking during the meeting, Deanna Kroetz, a biopharmaceutical sciences and pharmaceutical chemistry researcher at the University of California at San Francisco, noted that since 2004 there have been no less than nine drugs that have had label changes based on new genetic information. But such changes don’t always translate into changes in the way drugs are prescribed and dosed, she explained.
The first example Kroetz gave was 6-mercaptopurine or purinethol, a drug used to treat acute lymphoblastic leukemia. While most individuals can convert the drug to active metabolites using an enzyme called thiopurine methyltransferase, some individuals carry a deficient version of the enzyme. For these patients, 6-mercaptopurine treatment can lead to severe adverse drug reactions and an increased risk of infection.
Researchers first recognized variability in TPMT activity nearly 30 years ago. And since then, the genetics behind that activity were uncovered. Eventually, the US Food and Drug Administration recommended TPMT testing for purinethol, though such testing is not required. And most ALL patients aren’t tested for the risky TPMT variant. Kroetz said, even though a recent cost-effectiveness analysis indicates that such testing would be beneficial.
Kroetz also outlined the situation so far with respect to warfarin treatment. Warfarin, a much more widely prescribed drug, is an anticoagulant that must be carefully dosed to prevent under-dosing or over-dosing, which can lead to major bleeding events.
Several studies suggest variants in CYP2C9, the gene coding for cytochrome P450, and VKORC1, which codes for vitamin K1 2,3-epoxide reductase subunit 1, can influence an individual’s warfarin response. Together, CYP2C9 and VKORC1 account for roughly 55 percent of the variability in warfarin response, Kroetz said.
There is still heated debate among physicians over warfarin genetic testing, Kroetz said. A recent study concluded that warfarin genetic testing was not cost effective for initial warfarin dosing except for certain high-risk patients. As for purinethol, the FDA recommends but does not mandate that physicians perform genetic testing before prescribing warfarin.
On the other hand, Kroetz noted, physicians have been much quicker to adopt genetic testing to guide abacavir treatment. Individuals with specific forms in the HLA-B*5701 allele are hypersensitive to the HIV drug, which came on the market just over a decade ago. Last summer, the FDA recommended HLA-B*5701 genetic testing for abacavir treatment.
Kroetz speculated that the acceptance of genetic testing for abacavir may be due, at least in part, to the fact that physicians treating HIV patients regularly have to deal with rapidly changing drug regimes. That may make them more willing to use a new genetic test and follow new guidelines, she argued.
Even so, Kroetz said there are several factors that account for whether genetic associations lead to changes in the clinical application of a drug. Before a test is implemented, she added, research must be done to provide evidence that the genetic test is beneficial. FDA guidance, an appropriate cost-benefit analysis, willing and educated physicians, and other parameters also influence the translation of such research.
Despite the hurdles that must be overcome, Kroetz said increased research and discussion should ultimately facilitate a transition from pharmacogenetic research to clinical practice.