Development of an Interconnected Gut-Liver Model of Primary Human Origin Using Microphysiological Systems (MPS) for ADME Studies

Absorption, Distribution, Metabolism, and Excretion (ADME) are important parameters to determine the pharmacokinetic profile of a drug, and therefore a crucial measurement for drug efficacy. Animal models and immortalized cell lines have long been considered the standard preclinical tools for estimating a drug’s ADME profile for humans. Yet, 90% of newly developed therapeutic agents still fail to gain market entry, predominantly because the current preclinical methods – 2D cell culture and in vivo testing, fail to adequately predict a drug’s safety and efficacy in humans.

With recent advancements in science, a growing number of regulatory bodies are investigating and integrating the use of new approach methodologies (NAMs) into Drug Discovery workflows. In particular, microphysiological systems (MPS), also known as organ-on-a-chip (OOC), have elevated the preclinical toolbox. By combining primary cells with a fluidic flow, MPS models allow for more physiological relevance, as well as improved translatability of preclinical studies. We have established an interconnected Gut/Liver MPS model using our bespoke Multi-Organ OOC system. The model’s inter-organ crosstalk capabilities facilitate ADME studies to better predict oral bioavailability of a drug compound.

To improve on current in vitro gut models, that mainly use Caco-2 cells, we integrated a primary gut model (RepliGut®) into our MPS model. By developing a specialized co-culture media, we successfully preserved the functionality markers of both the gut and liver for at least 48 hours. Combined with primary liver cells, the model shows greater genotypic and phenotypic relevance to humans, when compared to immortalized cell lines. Finally, the model was dosed with drug compounds- temocapril and midazolam, which demonstrated improved predictive capacity of their ADME profiles.

To conclude, this primary Gut/Liver-on-a-chip model enables us to study the combined effects of intestinal absorption and hepatic metabolism. This demonstrates the potential of MPS as an alternative to standard preclinical methods to better estimate ADME profiles of compounds. With the use of these more predictive models, drug developers can gain earlier insights, thereby promoting a more cost effective and successful pipeline.

Learning Objectives: 

1. Summarize the benefits and challenges of current preclinical methods in drug discovery and development.

2. Review new alternative methodologies (NAMs) and microphysiological systems (MPS) and their application areas.

3. Examine the potential of MPS to improve on in vitro to in vivo translatability of preclinical studies for oral bioavailability assessment.