A multiscale computational tool to simulate the PK of orally-administered drugs in the human GI tract
Project Summary/Abstract:
Most FDA approved drugs are administered orally, despite the complex process of oral drug absorption that is
difficult to analyze experimentally. Oral bioavailability is dependent on the interplay between multiple and
simultaneous processes that are dependent on both the drug compound as well as the physiological and
anatomical states of the user. Due to this complexity, computational models have emerged as a tool to
integrate these factors in an attempt to mechanistically capture and predict the process of oral absorption in a
robust and accurate manner. The current predictive models are generally 0D compartmental models and are
thus limited by simplified physiological characteristics of the gastrointestinal tract (GIT), by semi-empirical or
specific analytical solutions of dissolution profiles, and by insufficient descriptions of interactions between
delivery vehicles and the GIT. In particular, the absorption can be incorrectly modelled using the 0D models for
(i) some drug classes (under the BCS scheme), (ii) for GIT, whose sizes are significantly different from the
median human and (iii) for drugs, that are meant to target specific regions (for instance, the drugs used to treat
some colon cancer) by incorrectly predicting the absorption in other regions. In this project, we propose to
develop an efficient and spatially accurate computational tool to simulate the dissolution, transport, Liberation,
Absorption, Distribution, Metabolism, Elimination, and Toxicity (LADME-T) of orally administered drugs in the
human GIT at the enzyme, delivery-vehicle, intestine-tissue, and GIT levels. This will be further combined with
the compartmental model at the whole-body level to predict systemic pharmacokinetics. In Phase I, the multi-
scale computational tool will be constructed by integrating the spatially accurate first-principles driven high-
fidelity drug transport, dissolution and absorption model in the human stomach and GIT, mechanistic drug
release models, and the multi-layer intestine physiologically-based pharmacokinetics (lumen, enterocyte, and
blood layers) models. These will be accomplished using the recently demonstrated CFD Research
Corporation’s spatially accurate Q3D framework. In Phase II, we will (i) test and validate the models for drug
transport and absorption physics for the 4 BCS classes of drugs, (ii) morph the GIT to create variants
corresponding to diseased specimens and different anatomical sizes, (iii) perform and validate the spatially
accurate drug absorption simulations for these new GIT variants, (iv) obtain the PK parameters and perform
the drug absorption simulations for infants and children, (v) link the Q3D GUT model to the whole body PK
model, and (vi) use this multiscale model, to optimize specific cases, including the drug delivery to target
regions. The multiscale software developed in this project will provide a powerful virtual platform in
investigating LADME-T, facilitating in vitro-in vivo scaling, designing and developing targeted oral drug delivery
systems, and evaluating safety and efficacy of oral drug products. Ultimately, the proposed tool will be
developed into a commercial product to meet urgent demands from pharmaceutical and biomedical industries.
