The physiological properties of the gastrointestinal tract, such as pH, fluid volume, bile salt concentration, and gastrointestinal transit time, are highly variable in vivo. These properties can affect the dissolution and absorption of a drug, depending on its properties and formulation. The effect of gastrointestinal physiology on the bioperformance of a drug was studied in silico for a delayed-release pantoprazole tablet and an immediate-release dolutegravir tablet. Physiologically based absorption models were developed and virtual clinical trials were performed. Reasons for the variability in drug bioperformance between subjects were investigated, taking into account differences in gastrointestinal tract characteristics, pharmacokinetic parameters, and additional parameters (e.g., permeability). Default software parameters describing gastrointestinal physiology in the fasted and fed states, and variation in these parameters, were altered to match variability in these parameters reported in vivo. The altered model physiologies better described the variability of gastrointestinal conditions, and therefore the results of virtual trials using these physiologies are likely to be more relevant in vivo. With such altered gastrointestinal physiologies used to develop models, it is possible to obtain additional knowledge and improve the understanding of subject-formulation interactions.