Abstract
BackgroundWomen experience adverse drug reactions, ADRs, nearly twice as often as men, yet the role of sex as a biological factor in the generation of ADRs is poorly understood. Most drugs currently in use were approved based on clinical trials conducted on men, so women may be overmedicated. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs.MethodsSearches of the ISI Web of Science and PubMed databases were conducted with combinations of the terms: drugs, sex or gender, pharmacokinetics, pharmacodynamics, drug safety, drug dose, and adverse drug reaction, which yielded over 5000 articles with considerable overlap. We obtained information from each relevant article on significant sex differences in PK measures, predominantly area under the curve, peak/maximum concentrations, and clearance/elimination rates. ADRs were identified from every relevant article and recorded categorically as female-biased, male-biased, or not sex-biased.ResultsFor most of the FDA-approved drugs examined, elevated blood concentrations and longer elimination times were manifested by women, and these PKs were strongly linked to sex differences in ADRs. Of the 86 drugs evaluated, 76 had higher PK values in women; for 59 drugs with clinically identifiable ADRs, sex-biased PKs predicted the direction of sex-biased ADRs in 88% of cases. Ninety-six percent of drugs with female-biased PK values were associated with a higher incidence of ADRs in women than men, but only 29% of male-biased PKs predicted male-biased ADRs. Accessible PK information is available for only a small fraction of all drugsConclusionsSex differences in pharmacokinetics strongly predict sex-specific ADRs for women but not men. This sex difference was not explained by sex differences in body weight. The absence of sex-stratified PK information in public records for hundreds of drugs raises the concern that sex differences in PK values are widespread and of clinical significance. The common practice of prescribing equal drug doses to women and men neglects sex differences in pharmacokinetics and dimorphisms in body weight, risks overmedication of women, and contributes to female-biased adverse drug reactions. We recommend evidence-based dose reductions for women to counteract this sex bias.
Highlights
Women historically were excluded from clinical pharmaceutical trials because of potential risks to individuals of childbearing potential
The present review study inventories drugs that elicit different responses in women and men and considers sex differences in adverse drug reactions (ADRs) that occur in individuals treated with therapeutic doses of medications
To determine the extent to which sex as a biological variable has been incorporated in the development of therapeutic pharmaceuticals, we reviewed whether sex differences in PK data were identified for any given drug and, where present, if such differences were incorporated into recommendations for sex-aware dosing/prescribing
Summary
Women historically were excluded from clinical pharmaceutical trials because of potential risks to individuals of childbearing potential. Remediation by the US National Institute of Health (NIH) Revitalization Act of 1993 mandated enrollment of women in federally supported phase III clinical trials; a European Union initiative provided practical tools regarding sex differences in drug study design [1]. The inclusion of women in clinical research subsequently increased in the USA, the EU, and Australia [1,2,3,4], most studies did not provide sexspecific data analyses [5, 6]. A 2018 review of 107 NIH funded randomized control trial studies that enrolled both men and women found that only 26% reported even one outcome by sex or included both sexes as a covariate [7]; 72% did not include sex in their analyses. We determined whether sex differences in drug pharmacokinetics, PKs, predict sex differences in ADRs
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