Project Objectives

• Establish and validate a standardized human organoid-based drug permeability assay using the AX12 organ-on-chip platform.
• Analyse a panel of clinically characterised reference drugs to evaluate predictive validity.
• Compare organoid permeability results with classical Caco-2 assays and clinical data.
• Integrate in-vitro to in-vivo extrapolation modelling to translate in-vitro data into human-relevant pharmacokinetic parameters.
• Develop SOPs suitable for regulatory consideration for intestinal and blood-brain barrier permeability assays.
• Engage regulatory and industrial stakeholders to support future adoption and guideline development.

3Rs Impact

• Creates a human-relevant alternative to animal-based Drug Metabolism and Pharmacokinetics (DMPK) assays used widely in early drug development.
• Could reduce approximately 20,000 rodent studies per year in Switzerland that are currently used in PK and permeability testing.
• Reduces long-term reliance on non-human primates for blood-brain barrier penetration studies by improving human-specific prediction.
• Generates standardised, validated datasets to shift industry and regulatory confidence toward animal-free approaches.
• Supports future inclusion of organoid-based assays in international regulatory guidelines.

Background

Drug absorption and distribution studies, often referred to as DMPK assays, are mandatory components of every new drug development programme. Currently, these tests rely heavily on animal models, even though species differences frequently limit their predictive value. At the same time, regulators such as the FDA have created pathways for drug applications that do not require animal testing, increasing the need for reliable human-based systems. Human intestinal and blood–brain barrier organoid models offer promising in-vitro options, but their broader adoption has been hindered by variability, lack of standardization, and insufficient validation against real clinical data.

This project aims to close that gap by using established human organoid models, selecting clinically well-characterised reference drugs, and validating permeability measurements using rigorous analytical and computational approaches. Close collaboration with regulatory bodies, labware manufacturers, and DMPK industry experts ensures that the project aligns with regulatory expectations from the outset. By combining organoid assays with in silico in-vitro to in-vivo extrapolation modelling, the project aims to create a predictive and standardised workflow that could replace a substantial portion of animal-based pharmacokinetic testing.