Dissolution and Absorption Modeling: Model Expansion to Simulate the Effects of Precipitation, Water Absorption, Longitudinally Changing Intestinal Permeability, and Controlled Release on Drug Absorption

Abstract A previously described model for simulating drug dissolution, absorption, and pharmacokinetics has been expanded beyond the original application of simulating immediate-release dosage forms to include simulation of drug precipitation, water absorption from the gastrointestinal tract, changing gastrointestinal permeability, disintegration, and controlled-release and dissolution from a GITS-type dosage form. A mathematical description of the model is presented as well as a retrospective analysis of nifedipine to demonstrate the utility of the model. The fourth-order Runge-Kutta numerical method was used to solve the series of coupled differential equations used to simulate the process of dissolution, absorption, and drug disposition. The model was able to simulate the clinically demonstrated effect for drug particle size on nifedipine plasma concentrations for an immediate-release dosage form. Further simulations indicated that drug particle size was less important for a GITS-type dosage form at a release rate of 1.7 mg/hr compared to rate of 17 mg/hr. Hypothetical calculations simulated the potential effect of drug precipitation, water absorption, and changing permeability on drug plasma concentrations. The expanded model increases the utility of a previously described model in providing guidance in drug development and selection.