Scientists Study Gender Gap in Drug Responses
Medical researchers have uncovered a startling and disturbing fact: Many prescription drugs seem to work very differently in women than in men.
Scientists still do not know why, but hormones, weight and metabolism are among the chief suspects. Whatever the causes, researchers are convinced that understanding the differences between how men and women respond to drugs holds the key to new knowledge and safer medicines for everyone.
“That’s really the core--by unlocking these kinds of scientific gender mysteries, we can apply them to developing medications that are safe and that work in all individuals,” said Marietta Anthony, an official of the women’s research program at the National Institutes of Health. “For the first time, we are documenting that men and women respond differently to drugs and sometimes with serious consequences, including death.”
The NIH last month convened a two-day meeting on the topic so scientists could compare notes and discuss future research. And in the last year, since the Food and Drug Administration started requiring companies to conduct gender studies on all applications for new drugs, the field has begun to heat up.
Lessons about the baffling gender differences have come the hard way from recent experiences with experimental drugs and, tragically in some cases, from drugs already on the market.
One experimental drug, for example, which at first seemed a perfect antidote for a rare form of stroke, worked spectacularly in men--and not at all in women. Eventually it was approved for sale in several European countries, but only for use by men. And it still is not on the market here.
Another drug--the once-popular allergy medication Seldane, which was removed from the market in 1997--was found to cause life-threatening cardiac arrhythmias resulting in some deaths when taken with certain other drugs.
Heart Problems Worse in Women
Looking at the data, experts discovered that these heart problems were striking women twice as often as men.
“We missed it at first,” said Dr. Raymond L. Woosley, chairman of the pharmacology department at Georgetown University. “It took a while before it became clear. But then we realized this is too much to be a coincidence. There has to be a biologic basis for this.”
The government first spotlighted these kinds of reactions in 1993, when the FDA took aim at an old policy that banned clinical studies involving women of child-bearing age. Researchers feared that testing drugs in young women might do harm to unborn children. And they thought that women’s hormones might interfere with their findings. It is that very “interference” that now is under the microscope.
The new research on gender differences could have a significant effect on the way physicians prescribe drugs--identifying vulnerable women and protecting them from dangerous side effects.
Drug companies are sponsoring their own research in hopes of averting medical disaster, every drug company’s worst public relations nightmare. In fact, they have no choice: The FDA last August imposed a new rule that no new drug will be approved for the market unless the application for its use includes information on how it affects each gender.
“It’s a very exciting area of science,” said Ruth Merkatz, director of women’s health for Pfizer Inc., who first brought the gender issue to the FDA’s attention when she worked for the agency in the early 1990s. “By probing some of these questions, we will learn more about how women’s bodies work and more about how men’s bodies work.”
Although drug industry officials generally agree that further research is needed, not everyone is convinced that the problems truly result from gender.
Other Factors May Be to Blame
Differences in drug reactions that are now being attributed to gender might well result from other factors, said Dr. Bert Spilker, vice president for scientific and regulatory affairs for the Pharmaceutical Research and Manufacturers of America, an industry group.
“We used to say that the elderly responded to drugs differently--and they do. But it was not because of age but because of other factors: social isolation, poor hygiene, poor sanitation, multiple drugs, other underlying diseases,” Spilker said.
Similarly, differences between men and women might prove less about gender and more about weight or any of a number of factors. Which is why, he said, differences that show up now in lab tests “are important and should be followed up.”
Knowing that differences exist is one thing. Understanding why and how they affect response to drugs is another--one that is drawing interest from researchers.
“The sad truth is that, even after all the clinical development that occurs with every drug and even after drugs have been approved for a long time, we only have a crude idea of what they do in people,” said Dr. Janet Woodcock, director of the FDA’s center for drug evaluation and research. “We don’t really know why they work well in some people and not as well in others.”
When it comes to women and how their responses compare to men, most experts agree that multiple factors are likely involved, among them hormones, metabolic rates, body weight, pregnancy, age and whether they are taking hormone replacement therapy.
Recent studies, for example, have shown that women respond differently to pain. They seem to have a higher pain threshold, meaning that they need lower doses of pain relievers to get the same effect as men. But physicians do not typically prescribe lower doses, which could be a danger.
Women also metabolize drugs differently than men. This fact landed hard in late 1994 at the Upjohn Co. (now Pharmacia & Upjohn) when researchers examined the results of a large European study of its experimental drug, tirilizad.
The compound seemed to be a promising treatment for subarachnoid hemorrhage, a form of stroke that afflicts more women than men, including young women, sometimes after they suffer a head injury.
The study involved more than 1,000 patients and the results were a shock, according to one former company official. “The drug was spectacularly successful in reducing mortality in men but not in women,” said Dr. Art Atkinson, who worked at Upjohn for several years beginning in 1994 and is now at NIH.
Further investigation revealed that “young women metabolized the drug 40% faster than men,” Atkinson said, explaining that the drug was cleared by their bodies too quickly to have an effect.
Additional studies have raised other questions about the drug and its outlook in this country remains uncertain. Still, “it would have been nice to know there was a sex difference before those initial studies were done,” Atkinson said.
The evidence was far less obvious with Seldane, a top-selling allergy drug that had been used by millions.
The first case, in 1989, involved a woman who blacked out while driving and was found to be suffering a rare and life-threatening cardiac arrhythmia. She had been taking two drugs, Seldane and ketoconazole, an anti-fungal medication.
Experts assumed, correctly, that the problem was caused by drug interaction. There were more cases, some involving Seldane taken with erythromycin, an antibiotic. When Woosley and others examined the data, they were struck by the numbers.
“Two-thirds of the cases were women,” said Woosley, who had seen similar arrhythmias among women taking other drugs.
Today Woosley believes that there may be as many as 40 drugs on the market that can produce these cardiac problems among certain women.
Researchers do not know yet why this happens. Many believe it is related to the “QT” interval--the time it takes for the heart’s electrical activity to return to its normal baseline between heartbeats.
Until puberty, men and women have the same QT interval. After puberty, men’s QT interval gets shorter.
“We knew in the 1920s that the QT interval in women was longer, but nobody--not until two or three years ago--ever asked why,” said Woosley, who recently received a five-year NIH grant to study the influence of hormones on drug sensitivity.
The higher profile of gender-based science is a welcome change for Woosley, who probably has been studying the problem longer than anyone.
“For a long time, I felt lonely,” he said. “Other scientists used to say: ‘Why are you wasting your time?’ It’s not a waste of time. Lives have been lost. And now that there is increasing awareness, lives will be saved.”
