How Drug Tolerance Differs for Women

This is the main conclusion of a large American study just published in Biology of Sex Differences, which analyzed literature data from more than 5,400 references to determine whether gender differences in pharmacokinetic parameters predict differences in the occurrence of adverse events in men and women.

Overall, women experience twice as many drug-related adverse events as men.

Many factors contribute to this difference in drug response between men and women. Women are more often taking multiple medications (2 or more) compared to men, and also more frequently taking a single medication (5 per year versus 3.7 on average for men).

Several parameters are likely to have an impact on the pharmacokinetics of a drug in women: they often have a lower weight than men, smaller organs, and a greater body fat mass, all of which will have an influence on drug absorption and distribution. Furthermore, the clearance of a drug is strongly linked to the expression of enzymatic systems which can vary according to gender. Renal clearance of drugs is decreased in women due to a lower glomerular filtration rate than men. Other peculiarities are observed in women: slower gastric emptying time, lower gastric pH, lower plasma volume, differences in body mass index, mean organ perfusion, total body water content. Finally, physiological hormone variations occurring throughout a woman’s cycle may also affect drug response.

In the context of their literature review, the authors identified 86 drugs for which significant differences in pharmacokinetic parameters existed between men and women on the basis of peak concentration values (Cmax), area under the curve, and distribution and elimination rates. For 76 of these 86 drugs, pharmacokinetic parameters were higher in women. Among the 59 drugs for which adverse event data was available, gender-related variations in pharmacokinetic parameters were predictive of variations in adverse events for 52 of them, or 88%. Ninety-six percent of the drugs for which there were variations in pharmacokinetic parameters in women were associated with a higher incidence of adverse events compared with men, whereas this percentage was only 29% in men. Thus, variations in pharmacokinetic parameters appear highly predictive of adverse events in women but not in men.

This means women are exposed to higher drug concentrations and longer elimination times than men. This most likely contributes to the nearly two-fold higher incidence of adverse events in women compared to men. For drugs with a sufficiently broad therapeutic index, these observations suggest that decreasing the dose may reduce the incidence of adverse events.

Based on the results of their analysis, the authors make several recommendations:

Recommendation 1. For commonly used medicines, health authorities should give health professionals access to the pharmacokinetic data submitted in the application that led to the marketing authorization, as well as the related publications. This would make available any gender-related differences in pharmacokinetic parameters and facilitate implementation of measures to reduce adverse effects in women.
Recommendation 2. Differences in pharmacokinetic parameters should be mentioned in the summary of product characteristics. Gender differences in adverse events could be mentioned in certain materials, such as pharmaceutical company websites or other institutional sites.
Recommendation 3. Where possible, dosages should be adjusted according to weight (mg/kg) for both men and women.
Recommendation 4. Health authorities should require that the data presented in the marketing authorization application meets the requirements for publication in a peer-reviewed journal.
Recommendation 5. The clinical importance of these gender-based pharmacokinetic differences must be well understood and addressed by healthcare professionals and should be a topic in continuing education.
Recommendation 6. Parity must be reestablished in the research context because women remain under-represented in clinical trials.
Recommendation 7. From the earliest stages of development, the pharmaceutical industry must focus on defining appropriate drug dosing based on sex.
Zucker I, Prendergast BJ. Sex differences in pharmacokinetics predict adverse drug reactions in women. Biology of Sex Differences. 2020, 11:32 https://doi.org/10.1186/s13293-020-00308-5

Women’s Cardiovascular Healthcare Foundation’s mission is to alert and guide health professionals so they can act in their sphere of influence to prevent cardiovascular disease among women, which has become their leading cause of death.