A Novel Colon PBPK Model: Navigating the Rational Drug Design for Small-Molecule Colon-Selective Therapies

Developing small-molecule colon-selective therapies for localized drug action is an attractive strategy in treating colonic diseases. Due to the lack of a reliable approach to understand human colon exposures, there have been few successful examples of clinically validated colon-targeted drugs. In this study, we aim to develop a physiologically based pharmacokinetic modeling approach that guides molecular design, formulation selection, and clinical trial design of small-molecule colon-selective therapies. We focus on the colon selectivity achieved through high hepatic extraction and modified release formulation, which are most likely to be predicted with confidence currently. With the established model, sensitivity analyses have identified compound and formulation design principles for achieving desirable colon-to-systemic selectivity. We have also demonstrated how the model can be used to guide first-in-human and late-stage clinical trials design. Overall, the established approach helps to facilitate rational drug design and clinical trial design for small-molecule colon-selective therapies.