Combining liver, kidney and gut-on-chip to predict human pharmacokinetics in vitro

Each year, tens of thousands of compounds are studied by the pharmaceutical industry. Lack of efficacy and safety are the most common reasons for drug failure during development, with over 90% failing in the costly clinical phase studies.

Drug disposition is tested by studying drugs’ pharmacokinetics (PK; the fate of a compound in the body), which can differ significantly between laboratory animals and humans. The US Food and Drug Administration (FDA) and the UK’s National Centre for the 3Rs (NC3Rs — reduction, refinement, and replacement of animal studies) estimate that 0.2 to 1.5 million animals are used annually by the pharmaceutical industry for PK testing.

Currently available and widely used cell-line based models also have limitations in predicting human drug absorption, distribution, metabolism, and excretion (ADME), which together define pharmacokinetics. This highlights the need for improved preclinical models.

Over the past decade, two exciting advancements have emerged in the in vitro field:

1. The 3D culture of mini-organs (organoids) derived from human cells that physiologically mimic human organs.
2. The development of organ-on-chip (OoC) technology, where cells are exposed to microfluidic streams in a 3D-fabricated system simulating human body fluid dynamics.

Using these innovations, we designed and constructed a system that connects different organ model systems to simulate drug uptake, transformation, and elimination. After absorption from the gastrointestinal tract, drug compounds are distributed throughout the body, can be chemically modified in the liver, and are excreted via bile (liver) and/or urine (kidneys).

A prototype organ-on-chip was developed for each of the four organ systems and optimized to exhibit key, organ-specific pharmacokinetic characteristics. The findings were presented at various international conferences.

We also developed a novel chip system allowing the modular coupling of two or more organs, which will be applied in more comprehensive multi-organ-on-chip (multi-OoC) studies to better predict human PK/ADME profiles.

As a proof of concept, we connected bioengineered kidney tubules to a liver organoid-on-a-chip. Testing with metformin showed a clinically relevant preference for renal clearance. A patent application for this system is currently being prepared.