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

By Wallace Ravven

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

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.