Quantitative Analysis of the Effect of Gastrointestinal Water Dynamics on Oral Drug Absorption using a Physiologically Based Integrated Liquid and Intestinal Absorption Drug (ILIAD) Pharmacokinetic Model

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Abstract
Purpose This study aims to develop a physiologically based pharmacokinetic (PBPK) absorption model incorporating gastrointestinal (GI) fluid dynamics and to quantitatively evaluate the effects of GI fluid dynamics on the oral absorption of various drugs in humans. Methods By incorporating our previously developed physiologically based fluid kinetic (PBFK) model describing GI fluid dynamics into a PBPK absorption model, we constructed the Integrated Liquid and Intestinal Absorption Drug (ILIAD) model, which dynamically describes drug concentrations based on the GI disposition of both fluid and drugs. The scaling factors (SF) for membrane permeability, CYP3A-catalyzed metabolism, and P-gp-mediated efflux introduced into the ILIAD model were obtained as common parameters for all drugs through simultaneous optimization using the reported plasma concentration–time profiles of atenolol, midazolam, and talinolol. Results Simulation analysis using the ILIAD model accurately predicted the bioavailability and plasma concentration–time profile of various CYP3A and/or P-gp substrate drugs. Sensitivity analysis demonstrated that changes in GI fluid dynamics can lead to variations in GI fluid volume, resulting in altered drug absorption, particularly for low-permeability drugs. However, further analyses demonstrated that even high-permeability drugs may be affected by the GI fluid dynamics when they are substrates of CYP3A or P-gp. Conclusion Our ILIAD model is expected to be a useful tool for predicting oral drug absorption properties, including the effects of changes in GI fluid dynamics.
Funding Information
  • Japan Society for the Promotion of Science (21J12535)
  • Japan Society for the Promotion of Science (24K02191)
  • Takeda Science Foundation

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