PROJECT SUMMARY
Lower-cost generic drugs generated approximately $2.2 trillion in savings to the US healthcare system in the
past decade. Therefore, generic drugs play a pivotal role in the sustainability of the US health system. A generic
drug is approved on the basis of sufficient demonstration of sameness to the corresponding brand-name drug.
Critical evidence for approval is bioequivalence (BE). Pharmacokinetics (PK) is the most commonly used BE
endpoint for systemically acting drugs since systemic exposure is upstream of the respective site of action.
However, the PK-based approach, if measurable, may not be sufficient for demonstrating BE for locally acting
drugs if there is a non-linear relationship between local and systemic exposures. Furthermore, systemic
variability may bias the retrospective assessment of local drug exposure. To the best of our knowledge,
concordance or discordance between systemic and local drug exposures has not been adequately addressed
in public domain.
Quantitative methods and modeling have been widely used in the realm of new drug discovery and development
to inform more efficient and cost-effective development programs. Physiologically-based pharmacokinetic
(PBPK) modeling is one of the key tools under the overarching umbrella of quantitative models. PBPK models
are an effective tool to integrate information about the product characteristics, the physiology of the individual
subject, and the variability among subjects within a population to simulate the local bioavailability throughout the
GI tract and subsequent systemic disposition of the drug without conducting in vivo PK studies. PBPK models
have shown promise in supporting generic drug development and regulatory decision-making, since, under a
model-integrated evidence perspective, it enables the leveraging of all prior knowledge generated to support the
regulatory approval of the respective brand-name drug product.
We will generate, analyze and integrate innovative in vitro data and PBPK modeling to assess the concordance
level between systemic and local drug exposures for drugs targeting the GI tract. The emerging model integrated
evidence framework will enable BE assessment at local and systemic levels. This will be done considering
healthy subjects and Crohn’s disease patients to test the hypothesis that (virtual) BE studies in healthy adults
can be safely generalized across target patient populations. We have excellent in vitro testing (and model-based
data analysis, i.e. SIVA toolkit) and PBPK modeling capabilities, along with unique replicate BE, PK, luminal drug
concentration data sets. Once established, this framework can also be extended to integrate prediction of local
exposure and intestinal epithelium life span to ultimately predict the time course of pharmacodynamic effects of
enterocyte-targeting drugs by integrating the nested enzyme-within-enterocyte turnover model into the
mechanistic M-ADAM model in the Simcyp™ simulator.
