Robotically handled whole-tissue culture system for the screening of oral drug formulations

Abstract

For nearly four decades cancer-derived cell line monolayers have served as the recognized standard for the modeling of gastrointestinal (GI) absorption and have been widely used as a tool for oral drug development. However, they show limited in vivo predictability. We have developed approaches to cultivate porcine GI tissue and enable it to function ex vivo for prolonged periods. We then created an interface design that can achieve fully automated high-throughput interrogation of whole segments of the GI tract. This GI Tract-Tissue Robotic Interface System (GI-TRIS) demonstrated high predictive capacity of human oral drug absorption (Spearman correlation coefficient of 0.906 vs 0.302 for Caco-2 cell based systems) while allowing a sample throughput of several thousand samples per day in a fully automated robotic facility. To examine the capacity of the GI-TRIS, we analyzed the intestinal absorption of 2930 formulations with the peptide drug oxytocin resulting in the discovery of a novel enhancer that resulted in an 11.3-fold increase in oral bioavailability of oxytocin in vivo in a large animal model while no disruption of the intestinal tissue was observed. In sum, the GI-TRIS system has the potential to transform oral drug formulation development and introduces the ORIS concept as a pre-clinical strategy for a wide range of applications.