FDA Grant for PBPK Modeling to Advance Bioequivalence Assessment of Locally-Acting GI Drugs

One specific objective of this project is to identify product quality attributes (formulation variables) and physiological or pathological variables that can influence the local and systemic bioavailability of locally-acting drug products in the gastrointestinal (GI) tract. Another specific objective of this project is to integrate predictive dissolution and PBPK models to assess whether they can support a demonstration of BE for generic locally-acting drugs in the GI tract. A general objective of this project is to assess whether model-integrated approaches using predictive in vitro data (e.g., dissolution data) may represent an alternative to comparative clinical end point BE studies when evaluating the BE of locally-acting drug products in the GI tract. Ideally, the proposal should include, at a minimum, plans for:

1) how to leverage currently available or to-be-developed (new) in vitro methodologies for drug release and dissolution when developing a PBPK model that utilizes the in vitro data to simulate and predict differences in product performance based upon formulation differences, including excipient effects in vivo. The proposed in vitro dissolution method is expected to utilize conditions that are representative of the physiological and/or pathological conditions at the site of action for the selected drug products.

2) how to (i.e., what data to use to) estimate between- and within-subject variability, as it is desired that the proposed PBPK model would be a part of virtual BE framework. It is expected that these variabilities would stem from variabilities in physiological factors, as well as the interaction/correlation between formulation-physiological factors. Strategies (specific approaches) for estimating the variabilities, particularly within-subject variability, and for simulating the effect of that variability on virtual BE studies should be clearly laid out, detailing a plan to evaluate these approaches.

3) how to assess model performance and credibility in predicting the local concentration of locally acting drug(s) in the GI tract. It is desirable that the verification and validation plan is included in the proposal.

4) how the virtual BE simulations would be conducted, described in detail (addressing both, systemic and local concentrations), including how the data will be analyzed, preferably within the modeling platform.

5) the dissemination of the outcomes of the research effort (e.g., presentations at scientific conferences, workshops, meetings and publications in scientific journals).

6) how to deliver the final developed model to the FDA Office of Generic Drugs (OGD), at a minimum, and preferably made public. Open-source code is preferable, but not required.