Personalized medicine: the promise, the reality: genetic testing can tell us how a patient will metabolize warfarin, but no one can tell us how to adjust our dosing

Journal of Family Practice, August, 2007 by Doug Campos-Outcalt

Genetic tests to guide warfarin dosing could avert 85,000 serious bleeding events and 17,000 strokes annually, according to a report from the AEI-Brookings Joint Center for Regulatory Studies, a Washington, DC, think tank. The report further suggests that by integrating genetic testing into warfarin therapy, American health care spending could be reduced by $1.1 billion annually. (1) Unfortunately, the promise of using genetic testing to guide such pharmacological treatment has largely gone unfulfilled. (2)

Case in point: Genetic testing can tell us whether a patient is likely to be an ultra-rapid metabolizer of warfarin (and need larger doses) or a poor metabolizer (and need lower doses), but there are no guidelines to tell us how to dose accordingly. International normalized ratios (INRs) still need to be ordered and the patient will likely have to pick up the tab for the genetic test ($250), since Medicare and private insurers don't cover the cost. (See "Warfarin: An ideal, but far from ready, candidate" on page 622.)

Hints that change may be on the horizon. The government--specifically the Department of Health and Human Services--created the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) to assess how genetic and genomic technologies are being integrated into health care and to identify opportunities and gaps in research. To that end, SACGHS issued a draft report earlier this year that notes that genetic-based treatment has "the potential to yield significant gains in personal health, population health, and cost-effective resource allocation." Among its many recommendations, SACGHS calls for greater collaboration between the public and private sectors to expand our knowledge of the clinical validity and utility of using genetics to guide treatment. (3)

A standard of care, potentially. Readying ourselves for the ways that genetics is likely to shape the way we prescribe such drugs as anticoagulants, antidepressants, and antiarrhythmics requires that we step back and assess the progress made so far, and the work that still needs to be done before genetic testing becomes a common occurrence, and perhaps even a standard of care.

* The goal: Avert adverse events

The wide variation in the way different people respond to the same dose of medications is a major contributor to the problem of adverse drug reactions. Lazarou and colleagues estimated that 6.7% of hospitalized patients--over 2 million patients in the US--experienced an adverse drug reaction and 0.32% (106,000) had a fatal adverse drug reaction. (4)

Individual response to medications is determined by a host of factors including age, environment, other medications being taken, and genetic differences in drug absorption and metabolism. These genetic differences have spawned the fields of pharmacogenomics and pharmacogenetics.

Pharmacogenomics is the biotechnological science that combines the techniques of medicine, pharmacology, and genomics and is concerned with developing drug therapies to compensate for genetic differences in patients, which cause varied responses to a single therapeutic regimen.

* A good example of pharmacogenomics at work is the use of trastuzumab in addition to chemotherapy for breast cancer patients who are positive for the human epidermal growth factor receptor 2 (HER2) oncogene. (5)

Pharmacogenetics is the branch of pharmacology that examines the relation of genetic factors to variations in response to drugs.

The use of pharmacogenetics to predict individualized responses to medications and to prevent adverse drug reactions through individualized dosing regimens or avoidance of certain medications hinges on our knowledge of genetic polymorphisms, that is, gene-based differences in drug absorption, distribution, metabolism, or excretion.

Polymorphisms of the cytochrome P450 family of drug metabolizing enzymes have been the most extensively studied. The names of these enzymes are abbreviated by using CYP and then a series of letters and numbers to describe individual enzymes. The 4 most extensively studied CYP enzymes are CYP2A6, CYP2C9, CYP2C19, and CYP2D6. These 4 metabolize an estimated 40% of all drugs; the distributions of polymorphisms of each vary considerably by race/ethnicity. (6-8)

A sampling of medications and classes of medications where polymorphisms play a significant role in drug metabolism is listed in the TABLE. Three with significant potential for prevention of adverse drug reactions are the antipsychotics, because of the severity of a specific drug adverse reaction, tardive dyskinesia; (6,9) warfarin, because of the risk of bleeding complications and its narrow therapeutic index; (7,10) and chemotherapeutic agents because of the serious nature of the disease and the potential for tailoring individualized therapies to maximize tumor response to medication and to minimize adverse reactions of very toxic drugs. (11)

* Clinical resources reflect an information gap

In spite of the potential for improved patient care, there remains very little clinical application of pharmacogenetic information in primary care practice. Zineh and colleagues reviewed prescribing information in the electronic version of the Physicians' Desk Reference (PDR) in 2004 and found that only 76 package inserts out of 3382 contained pharmacogenetic information. (12) In only 25 was there enough information to affect treatment decisions. Just 5 inserts mentioned that the chance of successful response to treatment could be predicted by genetic testing, and only one insert mentioned that a specific genetic subgroup should not take a drug.