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Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.The FDA Adverse Events Reporting System (AERS) is a voluntary database of adverse events. Based on an analysis of AERS data and other data resources, women experience more adverse events than men, and in general, these adverse events are of a more serious nature. The U.S. General Accounting Office (GAO) reviewed the ten drugs withdrawn from the market during the period January 1, 1997 through December 2000; eight of the ten were withdrawn due to greater risks of adverse effects in women.The FDA evaluated sex differences in bioequivalence among 26 studies submitted to the agency between 1977 and 1995. It is a major concern that over a 20-year period, only 26 studies submitted to the FDA had data addressing sex differences in drug absorption. Among the 26 studies, there were 47 datasets addressing sex differences in maximum concentration (Cmax) and AUC. None of the datasets had more than 20 individuals of each sex. Most had no more than 10 men or women, so the sample size available to assess sex differences in bioavailability was limited. However, among these studies, the Cmax was greater in women 87% of the time and AUC was greater in women 71% of the time.
Males and females may differ in specific drug pharmacokinetics and pharmacodynamics. It is, therefore, essential to understand those sex differences in drug disposition and response, as they may affect drug safety and effectiveness. To minimize therapeutic adverse events, clinicians and the pharmaceutical industry must establish clear therapeutic goals for the drugs of choice prior to treatment of women. It must be determined if the treatment should be assessed by clinical signs and symptoms or by laboratory test results whether drug toxicity will be evaluated by clinical or laboratory assessment, and what determines the appropriate duration of treatment. Furthermore, clinicians should be aware of and understand the principles of clinical pharmacology and absorption, disposition, metabolism, and elimination as they apply to the drug of choice. In particular, the prescribing physician should understand the relationship between drug dose, drug concentration and desired biological effect at the action site, the mechanism of action of the drug, the impact of the chosen drug on the patient’s signs, symptoms of adverse effects, and laboratory testing.
In general, data on sex differences are mostly obtained by post hoc analysis; therefore, the conclusions that can be drawn are limited. For a better understanding of the basic mechanisms of sex differences, future large-scale prospective studies should be designed with a primary focus on this topic. Although we have been able to articulate many of the sex differences in drug absorption, metabolism, and elimination, it is still necessary to identify the specific ADRs these differences can lead to as well as the mechanisms behind differences seen in pharmacokinetics and pharmacodynamics between the sexes. In particular, the potential for competitive hormone-drug interactions could provide us with more detailed mechanisms behind the pharmacokinetic differences seen between sexes. Further genetic studies in the context of drug toxicity and ADRs would contribute to our understanding of gender-specific pharmacokinetics. More specific data will help to determine the extent to which these differences will have implications for clinical management.