Sex Effect on Average Bioequivalence

Abstract

Purpose: Generic formulations are by far the most prescribed drugs. This scenario is highly beneficial for society because medication expenses are significantly reduced after expiration of the exclusivity period conceded to the branded name drug. Correspondingly, these formulations must be adequately evaluated to avoid drug inefficacy and toxicity in the overall patient population. Bioequivalence studies are the only in vivo evaluation that a generic drug must overcome to reach the market. These clinical trials have not been exempt from underrepresentation of female subjects and a lack of sex-based analysis. Frequently, conclusions obtained in men are extrapolated to women. Furthermore, the obtained results are not analyzed to determine sex differences. The aim of this study was to discuss the effect that male and female differences in gastrointestinal physiology can have on bioequivalence conclusions and to show why a sex-based analysis must be conducted in these studies to improve the evaluation of generic drugs.

Methods: This discussion was based on observed sex differences in product bioavailability discrimination (sex-by-formulation interaction) and on residual variability through an analysis of average bioequivalence data previously reported by other researchers and data collected by our center. Bioequivalence studies of oral formulations, with a 2-period, 2-sequence, 2-treatment random crossover design performed in healthy subjects with at least 6 subjects of each sex, were included. In addition, the bioequivalence conclusion that would have been reached in each study if performed with only 1 sex was estimated.

Findings: The data reveal that differences in both product bioavailability discrimination and residual variability occur with a significant incidence in bioequivalence studies. In either C_max or AUC, a significant sex-by-formulation interaction was present in 1 of 3 reviewed studies, whereas differences in residual variability between sexes were significant for >50% of studies. Moreover, the performed estimations suggest that the reported bioequivalence conclusions were not verified in at least 1 sex for 1 of 3 studies and were not verified in men and in women for 1 of 6 studies.

Implications: This research shows that extrapolation of bioequivalence results from the male population to the female population is not always valid. Bioequivalence studies must therefore be performed with both male and female subjects in similar proportions. Sex-based analysis in bioequivalence can improve study design, enhance the representativeness of conclusions, and provide important information regarding formulation performance, thereby promoting the efficacy and safety of generic drugs.

Keywords: bioavailability; bioequivalence; intrasubject variability; multisource drug products; sex-by-formulation interaction.