In Vitro-In Silico Modeling of Caffeine and Diclofenac Permeation in Static and Fluidic Systems with a 16HBE Lung Cell Barrier.

Static in vitro permeation experiments are commonly used to gain insights into the permeation properties of drug substances but exhibit limitations due to missing physiologic cell stimuli. Thus, fluidic systems integrating stimuli, such as physicochemical fluxes, have been developed. However, as fluidic in vitro studies display higher complexity compared to static systems, analysis of experimental readouts is challenging. Here, the integration of in silico tools holds the potential to evaluate fluidic experiments and to investigate specific simulation scenarios. This study aimed to develop in silico models that describe and predict the permeation and disposition of two model substances in a static and fluidic in vitro system. For this, in vitro permeation studies with a 16HBE cellular barrier under both static and fluidic conditions were performed over 72 h. In silico models were implemented and employed to describe and predict concentration-time profiles of caffeine and diclofenac in various experimental setups. For both substances, in silico modeling identified reduced apparent permeabilities in the fluidic compared to the static cellular setting. The developed in vitro-in silico modeling framework can be expanded further, integrating additional cell tissues in the fluidic system, and can be employed in future studies to model pharmacokinetic and pharmacodynamic drug behavior.