Continuing Education: Impact of Gender on Drug Responses
Davis, W Marvin, Drug Topics
A serious question for pharmacists should be, "How or when does gender affect pharmacotherapy?"
R. L. Woolsley, M.D., Ph.D., in Journal of Women's Health, 1998, concluded, "Only in recent years has it become apparent that there are clinically relevant differences between men and women in the way they respond to medications."
It is now acknowledged that drug development has long followed an almost exclusively male model, except when a therapeutic need quite distinctive to women was being targeted. However, as one female physician recently stated, "It is no longer acceptable to consider females merely as small males" and thus to extrapolate results of research on male subjects to women. Indeed, drugs formerly were prescribed for women despite their never being evaluated in women.
In 1993, the Food & Drug Administration issued a guideline indicating that drug development must include evaluation in both sexes. It emphasized checking for pharmacokinetic differences between male and female subsets, between pre- and postmenopausal women, and in different phases of the menstrual cycle. Attention was directed to evaluating potential drug-drug interactions, especially ones involving contraceptive steroids, with a possible reduction or loss of their effectiveness.
Furthermore, a prior injunction against phase I and early phase II testing (except for use in life-threatening conditions) in women having childbearing potential was revoked, although assurance against a subject's intention to become pregnant might be required. Previously, they could participate in those trials only if the drug was being evaluated for a life-threatening condition. A strong factor in this action was the recognition that women had been systematically excluded from clinical trials on drug therapy of coronary artery disease. Moreover, even when women had been included in trials, there often was no attempt to analyze data for possible sex-related differences.
Action to reverse this neglect began in 1992. Another outgrowth of the almost exclusive reliance of pharmaceutical development on clinical testing on male volunteers is that legal liability could ensue. An attorney wrote recently that pharmaceutical companies' policy of "Don't test, do sell" may open areas of legal liability for prescribers and dispensers of medications, in particular for the antiepileptic drugs (S. E. Herz, Epilepsia 1997; 38 [Suppl. 4]:S42 ).
Variations between the sexes (which may exist at birth) may derive from a direct influence of chromosomal sex on development. Alternatively, variations may arise only after sexual maturation in adolescence (by mediation of the sex steroids), and they may consist of either pharmacokinetic or pharmacodynamic factors.
A major aspect of human sexual dimorphism is that women generally have lower body weight (BW). This may require dose reduction to make dosage for women equivalent to that in men. In actual practice, however, body weight is rarely accounted for; it is assumed that any dose adjustment because of the BW factor would be too small to be clinically relevant. Indeed, this may often be true, except for drugs having an unusually low margin of safety. When adjustment for body mass is done, it could better be based on body surface area than weight-a common practice of dose determination for some highly toxic agents among the antineoplastic therapies.
There are numerous instances of pathologies that are specific to one sex or the other because of morphologic distinctions (neoplasias of the respective gonads or of the accessory structures, e.g., the uterus in women and the prostate in men) and of disorders that arise in, or from a dysfunction of, a sex-specific organ. These would include neoplasias and endocrine dysfunctions as well as responses to altered secretion of hormones from another organ. For women, this clearly includes changes over the menstrual cycle, during pregnancy, and before versus after menopause. …