Prediction Accuracy of Mechanism-Based Oral Absorption Model for Dogs

Abstract

The purpose of the present study was to evaluate the prediction accuracy of a mechanism-based oral absorption model for the fraction of a dose absorbed (Fa) in dogs, focusing on poorly soluble drugs. As an open mechanism-based model, the gastrointestinal unified theoretical framework was used in this study. The prediction accuracy of the gastrointestinal unified theoretical framework was evaluated using Fa data in dogs (63 data sets for marketed drugs and proprietary compounds). For neutral compounds, Fa was accurately predicted, suggesting that the physiological parameters of dogs were appropriate except for gastrointestinal pH. An extensive literature survey on the small intestinal pH of dogs was then conducted. The result suggested that the pH value ranged between 6.5 and 7.5, with the midst value of 7.0, but there was a great variation among the literature. To confirm the appropriateness of this pH value, the Fa of free acid compounds was predicted by setting the small intestinal pH to 6.5, 7.0, and 7.5. The proportions of compounds with <2-fold error were 57%, 90%, and 76%, respectively. The results of the present study would enable an appropriate use of a mechanism-based model for drug discovery and development.

Keywords: intestinal absorption; mechanistic modeling; oral absorption; pH; physicochemical properties.