By Clinical Research News Staff

August 14, 2020 | A new study from UC Berkeley and the University of Chicago suggests that women are more likely to suffer adverse side effects of medications than men, highlighting a disparity of representation in clinical trials.

The study, published in Biology of Sex Differences (DOI: https://doi.org/10.1186/s13293-020-00308-5), analyzed sex differences in drug pharmacokinetics (PKs) in order to predict sex differences in adverse drug reactions (ADRs).

“Women experience [ADRs] nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood,” writes the study’s authors, led by Irving Zucker from UC Berkeley’s Department of Psychology and Brian Prendergast from the University of Chicago’s Department of Psychology and Committee on Neurobiology. “Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated.”

Gathering data from the ISI Web of Science and PubMed databases, the researchers searched for articles that included the combination of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction. Caveats were included to narrow the search to relevant data, the authors explain; for instance, in order for a publication to be included it had to contain data on sex differences in PKs and/or ADRs. The search resulted in 5,000 articles with significant overlap.

“The correspondence of sex differences in PKs with sex differences in ADRs was striking,” the authors write. 88% of instances linked a sex difference in PK to a similar link in ADRs. The researchers suggest PK data, when considering ADRs, “greatly clarifies” patterns of sex differences in ADRs.

“In the absence of any obvious reason to suspect that our sample is not representative of the more than thousands of drugs approved for human use by the FDA, the present data suggest that elevated drug concentrations and decreased elimination times are far more prevalent in women than men and present a quantifiable and major health risk for women,” they conclude.

The study recommended seven ways to correct the representation disparities between the sexes. First, they recommend the FDA post PK data that were submitted as part of a current drug’s approval process on their website. “Once this information becomes accessible, scores if not hundreds of drugs with substantial PK sex differences will be revealed, which can facilitate corrective measures that will reduce female ADRs,” the authors write.

Second, they recommend any credible evidence of sex differences in PKs should be made available on drug labels. Popular websites for the general public, such as WebMD, should also list known sex differences when it comes to adverse effects.

Third, the initial dose of drugs with higher female PKs should be lower for women than men. “We anticipate this would eliminate or ameliorate many sex differences in adverse drug reactions,” the authors explain. “For orally administered drugs, pill splitting can begin to approximate a correction to the current practice where ‘one dose fits all.’”

Fourth, the FDA should require all empirical non-disclosure agreement (NDA) data to be accompanied by documentation of statistical analyses which should meet requirements for publication in a peer-reviewed journal. “Experiments reported in NDAs are less likely to be subjected to replication attempts by the scientific community, and therefore methodological or interpretive errors are less likely to be rapidly corrected by the iterative scientific process,” the authors write. Such data include a priori analyses, measures of central tendency, variance, etc. “Such information is essential if clinicians are to develop informed decisions regarding sex differences in drug effects.”

Fifth, the board certification process for healthcare providers should include an appropriate understanding of the clinical relevance of sex-differences in drug treatment. This should be reinforced with continual medical education courses.

Sixth, the Department of Health and Human Services should establish sex parity as a long term goal in the drug approval process. “The decades-long pattern of neglect of female animals in preclinical research and underrepresentation of women in clinical trials and research must be corrected, and the recent NIH oversight and vigilance must be maintained,” argue the authors.

Seventh, the study’s researchers recommend that pharmaceutical companies pay more attention to sex-appropriate dosing, beginning in the early drug development phases. “If, during the early stages of pre-clinical development, a compound is titrated or optimized specifically in male cells or in male mice, then any sex biases inherent in such models may be passed forward into later stages of drug development,” they write. “The disproportionate expression of increased PKs and ADRs in women may be one result of this continued neglect.”