The most common method for establishing bioequivalence (BE) is to demonstrate similarity of concentration–time profiles in the systemic circulation, as a surrogate to the site of action. However, similarity of profiles from two formulations in the systemic circulation does not imply similarity in the gastrointestinal tract (GIT) nor local BE. We have explored the concordance of BE conclusions for a set of hypothetical formulations based on budesonide concentration profiles in various segments of gut vs. those in systemic circulation using virtual trials powered by physiologically based pharmacokinetic (PBPK) models. The impact of Crohn’s disease on the BE conclusions was explored by changing physiological and biological GIT attributes. Substantial ‘discordance’ between local and systemic outcomes of VBE was observed. Upper GIT segments were much more sensitive to formulation changes than systemic circulation, where the latter led to false conclusions for BE. The ileum and colon showed a lower frequency of discordance. In the case of Crohn’s disease, a product-specific similarity factor might be needed for products such as Entocort® EC to ensure local BE. Our results are specific to budesonide, but we demonstrate potential discordances between the local gut vs. systemic BE for the first time.