Potential of tailoring drugs to genetic makeup confirmed--but challenges remain

November 13, 2001

At a time when harmful drug reactions are thought to rank just after strokes as a leading cause of death in the U.S., the potential benefits of tailoring drugs to a patient's genetic makeup have been confirmed in a systematic study led by University of California, San Francisco scientists.

The quantitative assessment of the promise of this new approach - known as pharmacogenomics -confirms that many harmful drug reactions previously thought to be non-preventable may now actually be averted using genetic information about patients to select their drug therapies.

The study, the first systematic assessment of pharmacogenomics' potential, is paired with an analysis of many remaining hurdles: questions about the effectiveness of the practice, inadequate training, funding and sites for carrying out patient genotyping; and the risk of creating inequities when developing drugs to avert problems caused by natural genetic differences linked to race.

The report appears in the November 14 issue of JAMA, the Journal of the American Medical Association.

The researchers first conducted two independent systematic literature reviews: one on studies reporting adverse drug reactions (ADRs) and one on studies reporting natural genetic variation, or variant alleles in genes for enzymes that metabolize drugs.

They then "linked" these two studies by focusing on the enzymes from the second search known to metabolize the drugs identified in the first search. This allowed them to assess the possible contribution of genetic variability to ADRs.

The results highlight a strong potential link between the genetic variants and adverse drug reactions. The scientists found that 59 percent of the drugs cited in the ADR study are metabolized by at least one enzyme with a naturally occurring variant known to cause poor metabolism.

Conversely, only 22 percent of randomly selected drugs sold in the U.S. and only 7 percent of randomly selected top-selling U.S. drugs are metabolized by enzymes with this genetic variability - differences greater than two-fold and eight-fold respectively.

"Our study confirms the powerful potential of genetic information to improve drug therapies, but it also emphasizes the importance of considering how genetics will affect both health care practice and the public," said Kathryn A. Phillips, PhD, lead author on the report and UCSF associate professor of health economics and health services research in the UCSF School of Pharmacy and the Institute for Health Policy Studies.

"In the future," the authors conclude, "we may all carry a 'gene chip assay report' that contains our unique genetic profile that would be consulted before drugs are prescribed. However, the application of pharmacogenomics information faces significant challenges, and further basic science, clinical and policy research is needed to determine in what areas pharmacogenomics can have the greatest impact, how it can be incorporated into practice, and what are its societal implications."

One of the societal implications they highlight stems from the fact that many genetic variants cluster in racial groups. As a result, it is inevitable that some fairly small racial populations in the U.S. have genetic variants making them particularly vulnerable to some drugs.

In some cases, drug manufacturers may not find it economical to develop a new drug to aid a small potential market. Such a confluence of pharmacogenomics and commerce could cause societal stress, the authors note.

Other hurdles are the limitations in the amount of genotyping now carried out, uncertainties about its cost and the limited number of clinicians now trained to take advantage of new pharmacogenomic information as it becomes available.

Finally, the authors point out that experts are not in agreement on the degree to which knowledge of a patient's genetic variants would actually make a difference in drug prescription because adverse drug reactions are caused by multiple factors and more needs to be known about the role of genetic variability.
The research was supported by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.

Co-authors on the paper are David Veenstra, PhD, PharmD, assistant professor of pharmacy, University of Washington; Eyal Oren, BA, and Jane K. Lee, research associates in the UCSF School of Pharmacy; and Wolfgang Sadee, PhD, UCSF professor of biopharmaceutical sciences.

University of California - San Francisco

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