(128g) Physiological Modeling of Gastrointestinal Tract for Predicting the Effect of Cyclodextrin on Bioavailability of Neutral Compounds

Oral delivery of low-solubility drugs is often problematic, resulting in lack of bioavailability. To enhance aqueous solubility and absorption, drug delivery technologies such as cyclodextrins are used. Cyclodextrins are cyclic oligosaccharides that form inclusion complexes with many hydrophobic drugs. It is possible for cyclodextrins to not affect or even hurt overall compound absorption if not formulated properly. Thus, predicting the influence of a drug delivery technology such as cyclodextrin on drug absorption using models of intestinal drug delivery can be beneficial in formulation design.

In modeling intestinal drug delivery, the GI tract is often considered as a single mixed volume of fluid. The GI tract can be represented more physiologically as a series of seven well-mixed compartments [1]. Models utilizing this representation were developed to predict the influence of CD dosed as a physical mixture and as a pre-formed complex with neutral drug on oral absorption and incorporated into MATLAB code. The models include mathematical expression for dissolution, complexation, absorption, precipitation and transit kinetics of drug dosed with CD based on mass transfer principles and assumed pseudo-equilibrium of complexation. The model input includes physical and chemical properties of drug, CD and GI tract that are parameters in model equations. Model output indicates absorption of drug with respect to time.

Model predictions indicate that CD will not enhance absorption when dosed as a physical mixture with drug, and will in fact hurt absorption by up to 40% for high solubility compounds. The physiological model predicts a greater decrease in absorption when dosing with CD as compared to the single tank model. However, it was predicted that CD dosed as a pre-formed complex will enhance absorption of high solubility compounds by up to 20%. For a pre-formed complex, the physiological model predicts less absorption enhancement than the single compartment model. These results indicate that the method of representation of the GI tract is important to predictions of the influence of drug delivery technologies on compound absorption. A pharmacokinetic model will be developed to predict the bioavailability of drug dosed with cyclodextrin using absorption input from the existing models, and the results will be compared to in-vivo studies.

[1] Lawrence X. Yu , John R. Crison and Gordan L. Amidon, Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. International Journal of Pharmaceutics (1996) 140 p. 111-118