Harnessing the Power of Physiologically Based Pharmacokinetic Modeling to Explore Potential Discordance between in vitro Dissolution, Local Gut vs Systemic Bioequivalence in Health and Disease: The Case of Budesonide in Crohn’s Disease

Abstract

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, the similarity, or otherwise, of profiles from two different formulation in the gastrointestinal tract (GIT) may not be associated with same conclusions based on systemic circulation. Here, we have explored the concordance of BE conclusions (or otherwise) for a set of hypothetical formulations based on drug concentration-profiles in various segments of gut vs those in systemic circulation using virtual trials powered by physiologically-based (PBPK) models. Moreover, by changing physiological and biological attributes of the GIT, the impact of Crohn’s Disease on the BE conclusions was explored. The virtual BE (VBE) was applied to an Entocort EC, a pH/time-dependent release formulation of budesonide, as model drug that is targeted at ileum and colon. Substantial “discordance” between the 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 with systemic-derived VBE. Nonetheless, a higher f2 value than the default similarity standard (50) was required to achieve local BE. In the case of Crohn’s Disease, a product-specific f2 value might be needed for drugs such as Entocort EC to ensure local BE, knowing the insensitivity of systemic data to show lack of BE. The results, being limited to the single model drug product, Entocort EC, may not provide a a general and conclusive picture. However, for the first time, it demonstrated the potential discordances between the local gut vs systemic BE.

Linking in vitro–in vivo extrapolations with physiologically based modeling to inform drug and formulation development

“…We anticipate a great connectivity between microphysiological systems and PBPK-PD modeling under the overarch of systems pharmacology (Isoherranen et al, 2019;Pineiro-Llanes et al, 2023). This might have implications for extrapolating the results of bioequivalence studies which are typically done in healthy volunteers rather than in the target patient groups (Chunyan Han et al, 2023). In fact, integrating patient-specific microphysiological systems and PBPK modeling may pave the road to move from virtual subjects to digital twins and further research in this field is rather welcome.…”