From hypothesis to forecasting: The impact of within-subject variability of gastro-intestinal physiology in relation to likelihood of sex-dependent outcome of bioequivalence

There are calls for inclusion of both sexes when conducting bioequivalence (BE) studies as this is not common practice for variety of reasons. There are not many proven cases for sex-dependent outcome of BE studies; hence inclusion of female participants in BE studies is considered as a matter of equity and principle. Most typical BE studies are cross-over design where between-subject variability (including sex effects) plays no role. However, within-subject variability (WSV) can still play a significant role, in passing the BE criteria. It has been shown that WSV of gastrointestinal (GI) tract as well as drug disposition factors propagate to the pharmacokinetics, defining the outcome of BE. By applying known sex-based differences in WSV measures of colonic transit time (CTT) and gastric emptying time (GET), we illustrate how hypotheses can be formulated regarding potential sex-dependent outcomes in BE studies. This approach supports informed decision-making on the necessity of including female participants or justifying prudent waivers for their inclusion. Virtual Bioequivalence (VBE) assessments were carried out (using VBE module in Simcyp V22 (Certara Predictive Technologies, Sheffield, UK)) where three hypothetical drugs product with distinct dissolution rates were evaluated against multiple virtual test formulation counterparts. The influence of sex-dependent WSV in CTT and GET on VBE outcomes was demonstrated by systematic analysis of discordance between BE in female vs. male subjects. The exercise provided a roadmap for generating hypotheses regarding the propagation of sex differences in physiology to BE outcome.