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In an article that appeared in Pharmacy Times in February 2004, I described gender-specific drug effects. 1 I explained that one of the reasons for these different effects is that men and women metabolize drugs differently.
Differences also exist in certain disease incidences between the sexes and among racial and ethnic groups. For example, the age-adjusted risk for incident coronary heart disease (CHD) is higher in African-American women aged 20 to 54 years than in Caucasian women of the same age and lower in African-American men than in Caucasian men of the same age.2 In addition, there are differences in the association between hypertension and CHD by sex and race.3 According to the American Heart Association, cardiovascular (CV) diseases rank as the number-1 killer of African Americans, claiming the lives of >37% of the >285,000 blacks who die each year. It is estimated that ~30% of non-Hispanic white men and 24% of non-Hispanic white women have CV disease. Among non- Hispanic blacks, ~41% of men and 40% of women have CV disease.
Because of the disparity, it would appear reasonable to use race as a factor when choosing drug therapy for patients. This disparity was made clear when the results of 2 studies were published in a major medical journal several years ago. The reports addressed the effects of race on the response to drugs of 2 important classes used in heart failure. One was a beta-blocker with alpha-adrenergic blocking effects (carvedilol),4 and the other was an angiotensin-converting enzyme (ACE) inhibitor (enalapril).5 Both drugs had been shown in multicenter, randomized, controlled trials to be effective for patients with heart failure. The characteristics of the patients most or least likely to benefit were poorly defined, however, so physicians lacked guidance as to the optimal therapy for patients of different racial backgrounds.6 It was demonstrated that carvedilol appears to reduce the risk of death or hospitalization in both black and nonblack patients, whereas the ACE inhibitor appears to reduce the rates of hospitalization only in whites.
Rationale For the purposes of this article, the terms race and ethnicity will be used interchangeably. Traditionally, race refers to differences of biology, ethnicity to differences of culture and geographic origin.7
Racial differences in drug responses have now been described for a range of drugs, and they reflect genetic differences, environmental differences, and fundamental differences in the pathogenesis of diseases.6 Many of the genetic differences are based on varying distributions of polymorphisms in drug receptors or drug-metabolizing enzymes among different racial and ethnic groups. (A polymorphism is a genetic variant.) For example, CYP2D6 is the cytochrome P-450 enzyme responsible for the metabolism of betablockers. Black Americans have a high frequency of a CYP2D6 allele that encodes an enzyme with impaired activity, which could affect alphaadrenergic blockade and result in toxic effects.6 (An allele is an alternative form of a gene that can occupy a particular location on a chromosome.) Black patients may lack nitric oxide, a chemical that plays a major role in dilating blood vessels. In addition, there appear to be racial differences in cardiac structure and function in untreated black patients with hypertension, when compared with untreated white patients.8 These differences may or may not have an effect on the use of drugs to treat this disorder.
Many gene variants are known to affect drug response, so it should be possible to predict drug response on the basis of race. Variants, however, that are present in one ethnic group are usually present in others as well.9 It has been claimed that at least 29 medicines, or combinations of medicines, have differences in either safety or, more commonly, efficacy among racial or ethnic groups. (An example is the recent finding that subgroups of Asian patients were observed with increased rosuvastatin drug levels. This was one of the reasons that the FDA required the manufacturer to make a lower dosage form available.)
In many cases, any reported differences in safety and efficacy claims for certain drugs are controversial.10 The hope is that the emerging science of genomics will offer a way to use race as a means to understand the causes of disease and to choose optimal drug therapy.11
Remarkable progress has already been made with certain drugs for CV disease. For the first time, a drug designed for "race-specific" therapy exists.12 The product, called BiDil, is a combination of the antioxidant hydralazine (37.5 mg) and the nitric oxide donor isosorbide dinitrate (20 mg). These 2 drugs have been used for years to treat heart-related problems. NitroMed, the manufacturer of BiDil, has obtained the first-ever patent for preexisting drugs for a new, race-specific use.
The manufacturer submitted a new drug application to gain FDA approval to market BiDil specifically as a heart drug for blacks. The reason is that the sponsor chose to test the drug in a major study exclusively limiting enrollment to black patients. The study, which involved >1000 patients at ~170 study sites, was stopped early after initial results showed a significantly higher mortality rate in the placebo group. At the time the trial was halted, 54 patients had died in the placebo group (10.2%) and 32 patients in the combination-therapy group (6.2%).13 The action followed unanimous recommendations from both the independent Data and Safety Monitoring Board and the Steering Committee for the trial.
Despite the results, critics contend that it is irresponsible and unscientific to imply that BiDil works better on people of one race than of another. It also means that a number of nonblack patients who might benefit from the drug will not receive it and that black patients may assume that it will help even if it will not. This could, of course, lead for the first time to "racial profiling" in medicine. There is also the danger that, as other drugs emerge with better results in one racial group or another, some pharmaceutical companies may be tempted to qualify them as racial medicines rather than broader- based therapies.14
Supporters think that the drug is a significant advance for treating black heart failure patients and that the most important consideration should be saving lives. The Association of Black Cardiologists (a joint sponsor of the study) and the Congressional Black Caucus have lauded the research effort.15
This is a real conundrum, but it was resolved when the FDA approved the drug on June 23, 2005, calling it a step toward the promise of personalized medicine. The Indications and Usage section of the package insert, in part, states that BiDil is indicated for the treatment of heart failure as an adjunct to standard therapy in self-identified black patients to improve survival, to prolong time to hospitalization for heart failure, and to improve patient-reported functional status.
Mr. Sherman is president of Sherman Consulting Services Inc.
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