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.