Development of PBBM Framework to Support an Assessment of Bioequivalence for Locally-Acting
Drugs in the Gastrointestinal Tract in Healthy Subjects and Patients – Project Summary
The goal of this project is to propose a new, validated model-integrated approach as an alternative to
comparative clinical endpoint bioequivalence (BE) studies when evaluating the BE of locally acting drug
products in the gastrointestinal tract (GIT).
This goal will be achieved through two paired elements: an in vitro component and an in silico component.
In vitro dissolution of GIT locally acting drug products currently approved on the market will be measured in
biorelevant dissolution media representing the healthy and diseased gut physiology. Additionally, formulation
variants will be created for three (3) APIs. Their dissolution properties will be tested in the same in vitro assays.
This effort will provide a first indication of the impact of product quality attributes on API dissolution/release in
patients. In parallel, the Advanced Compartmental Absorption and Transit (ACAT™) model, within
GastroPlus© physiologically based pharmacokinetic (PBPK) platform, will be adapted to account for GIT
disease conditions. Combining the in vitro dissolution results from currently approved GIT locally acting drug
products with the enhanced ACAT model, in vitro to in vivo relationships will be established to assess the
ability of the PBPK model to predict local and systemic exposures. Parameter sensitivity analysis (PSA) will
be performed to differentiate the relative importance of product quality attributes and pathophysiological
parameters on the local and systemic concentration time courses. Finally, a virtual BE approach will be used
to compare the test formulation variants with their respective references. Respective PK metrics at the site of
action and in plasma for the test and reference drug products will be compared to assess BE in both biophases.
The findings from this project will support the regulatory assessment of locally acting drug products for
GIT diseases by proposing a novel, model-integrated approach in lieu of the current BE practices. This
methodology will help to establish scientific and regulatory standards for supporting innovative development
and performing BE evaluation of these complex generic drug products.