Drugs and Gender Differences

by Food and Drug Administration (FDA)

(Page 2 of 4)

In 1998, the allergy drug Seldane (terfenadine) was removed from the market, when a safer alternative was approved. It had been discovered that Seldane could cause a life-threatening heart rhythm irregularity when used with certain other drugs. More women took Seldane, and more were reported to have had this heart arrhythmia, called torsades de pointes.

Researchers at the Georgetown Center for the Study of Sex Differences believe that the male hormone testosterone may protect the heart from some types of arrhythmia, says Verbalis. In addition, he says, research has shown that women are at greater risk for torsades de pointes because of their QT interval — ;the time it takes for the heart to relax after it contracts to pump out blood. Women often have a longer QT interval than men, and taking certain drugs can further lengthen this interval, thereby increasing the risk of the fatal arrhythmia more in women than in men.

Some drugs are approved to treat a disease based, in part, on patients' reporting of the relief of their symptoms. For example, Zelnorm (tegaserod maleate) is approved only for women to relieve the symptoms of IBS. In clinical trials, more women taking Zelnorm reported relief of their symptoms than those taking an inactive pill (placebo).

IBS, which is found more commonly in women, produces a variety of symptoms. "The challenge in the evaluation of a drug for this disease is to determine if there is a gender difference in the patient's perception of symptoms and evaluation of relief of symptoms," says Joyce Korvick, M.D., acting director of the FDA's Division of Gastrointestinal and Coagulation Drug Products. "The perception of 'relief' of symptoms in men and women may be very different."

Because IBS is found more often in women, more women than men were enrolled in the clinical trials for Zelnorm. But for the nearly 300 men with IBS enrolled in the trials, Zelnorm was not shown to be effective. "More research regarding men and women's perceptions of specific disease symptoms is needed to ensure that differences seen in clinical trials are meaningful to the gender being studied," says Korvick.

Another drug, Zoloft (sertraline hydrochloride), is approved for both men and women to treat several conditions, including post-traumatic stress disorder (PTSD). This approval was based on clinical trials in which Zoloft showed little effect in men with PTSD, while the drug's benefit over a placebo was clear in the women studied.

"True gender differences in responsiveness may have been one explanation," says Thomas Laughren, M.D., team leader for the FDA's psychiatric drug products group. "However, it should also be noted that the types of PTSD differed in the two groups," he says. Many of the men in these trials had a long-lasting and treatment-resistant PTSD, based on military combat experience, compared to many of the women who tended to have a more acute form of PTSD, based on recent physical abuse.

Scientists aren't sure why some drugs work better in one gender than in the other. But they do know that differences may occur in the way men and women absorb certain drugs into the bloodstream, distribute them to the body's tissues, break them down, and rid them from the body. The way the body handles a drug is known as pharmacokinetics (PK), and was the subject of an FDA study.

FDA researchers examined 300 drug applications submitted to the agency between 1994 and 2000. More than half of these applications contained information on the effect of gender on PK. The PK was the same for 80 percent of the drugs in which PK was studied. But for the other 20 percent of the drugs, the PK was different.

"There must be some reason for this difference," says Miller. "That's where research comes in. We want to understand the biology and the mechanism enough to predict what's going to be in the 80 percent group and the 20 percent group. Then we can predict how a product's safety or effectiveness will be influenced in each gender."

Shiew-Mei Huang, Ph.D., deputy director for science in the FDA's Office of Clinical Pharmacology and Biopharmaceutics, says that drug metabolism plays an important role in the way men and women respond to drugs. An enzyme known as cytochrome CYP3A helps metabolize many drugs, and studies have shown that women have more cytochrome CYP3A in the liver, says Huang. Some drugs or dietary supplements, for example, St. John's wort, increase the activity of this enzyme, which makes the drugs break down faster. This rapid breakdown reduces the amount of the drug in the body, decreasing its effectiveness in women.

The reverse scenario may also occur: A drug could slow down enzyme activity, causing too much of the drug to build up in the body and resulting in more side effects.

But biology can't explain all the differences in the way men and women respond to drugs, cautions Huang. Other factors, such as medication use, must be considered. "A recent survey showed that women, in all age groups, tend to take more medications, including dietary supplements, than men," says Huang. This difference may put women at more risk for certain drug interactions than men.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.