Exploring the Use of a Kinetic pH Calculation to Correct the ACAT Model with a Single Stomach Compartment Setting: Impact of Stomach Setting on Food Effect Prediction for Basic Compounds.

Advanced compartmental absorption and transit (ACAT) based computational models have become increasingly popular in the industry for predicting oral drug product performance. However, due to its complexity, some compromises have been made in practice, and the stomach is often assigned as a single compartment. Although this assignment worked generally, it may not be sufficient to reflect the complexity of the gastric environment under certain conditions. For example, this setting was found to be less accurate in estimating stomach pH and solubilization of certain drugs under food intake, which leads to a misprediction of the food effect. To overcome the above, we explored the use of a kinetic pH calculation (KpH) for the single-compartment stomach setting. Several drugs have been tested with the KpH approach and compared with the default setting of Gastroplus. In general, the Gastroplus prediction of food effect is greatly improved, suggesting this approach is effective in improving the estimation of physicochemical properties related to food effect for several basic drugs by Gastroplus.