In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction

Abstract

The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.