Sex-dependent outcomes of bioequivalence studies in the absence of any sex-by-formulation effects on the drug absorption: Examining theoretical possibilities

Arguments for including female volunteers in bioequivalence (BE) studies focus on achieving equity when drugs are intended for use in both sexes. Virtual bioequivalence (VBE) studies in female populations offer an alternative approach to address the gap, especially with ability to delineate likely differences in the outcome of BE using sex-related inputs in physiology and biology.

Whilst sex-by-formulation effects are suggested based on some animal studies, no research has comprehensively addressed sex-dependent BE outcomes, particularly in the absence of such effects on absorption. This study provides a theoretical background to potential sex-dependent outcomes in BE. It is demonstrated that, for a given difference between rate of absorption of a reference (R) and test (T) products, that is similar in both sexes, the impact on C_max as one of the BE assessment indices might be sex dependent. Various hypothetical scenarios within realistic boundaries of pharmacokinetic parameters [25–100% for absorption rate (k_a) of T vs. R, and up to 4-fold difference in elimination rate (k_e) between sexes] were tested. These simulations identified parameter spaces where BE outcomes diverged between males and females. The observed effects are linked to sex-dependent differences in elimination, influenced by variations in volume of distribution or enzyme abundance affecting clearance.