Translational preclinical ADME models for accurate drug development

InTESTine™ (pdf) and Intestinal Explant Barrier Chip (IEBC) can be used to investigate intestinal absorption and metabolism, drug-drug or food-drug interactions, or secretion of satiety hormones and neurotransmitters after exposure to pharmaceutical agents, biological substances, and nutrients in the intestinal wall.

These unique, physiologically relevant and medium-throughput systems can accommodate fresh, ex-vivo intestinal mucosal tissue of human or animal origin, so it closely resembles the in vivo situation. Besides studying processes that determine oral absorption across multiple and varied intestinal regions (duodenum to colon), the IEBC model can be applied to study the effects of compounds on gut health, inflammatory processes as well as interactions with the (specific) microbiota. Read more about microbial metabolite interaction.

TNO has implemented (sub)normothermic liver, kidney or combined liver-kidney perfusion to be applied as a preclinical ADME model. These models are expressly designed to predict pharmacokinetics behaviour of compounds in ways that in vitro liver or kidney models cannot, including hepatic extraction, biliary and renal excretion, metabolic clearance, and the effect of DDI on these processes. By using healthy porcine organs or discarded diseased human livers (during organ transplantation, for example, cirrhotic livers) the effect of disease status on ADME can be studied. Read more about explanted human liver model to assess hepatic extraction.

Many pharmaceutical companies use I-screen (pdf) to investigate potential metabolite formation by human colon microbiota, but the platform can also be applied to study the effect of compounds the microbiome composition or functioning. It employs physiological and anaerobic conditions to facilitate the culture of full-dense microbiota. Read more about the screening platform for microbiome-mediated drug metabolism, or how these type of models can applied in the development process.

The Competitive Partitioning to a Polymer Phase (ComP3) assay accurately measures the fraction unbound (fu) of (potentially) highly protein-binding and extremely hydrophobic compounds. The platform is based on a 96-well plate, easy-to-use, and applicable for upscaling to be applied as screening model for comparison of multiple APIs, species, and/or donor variation. It can be used to determine patient-specific plasma protein binding (or plasma/tissue partition coefficients for PBPK modelling) for hydrophobic small molecules, protein degraders, and hydrophobic peptides sensitivity of the assay Fu<0,01%.

TNO has the capabilities and facilities to incorporate a 14C label to enable advanced and investigational animal studies. Our BSL-2 labs have a radioactive C-licence, which means that 14C-labelled GMO cell lines, viral particles, etc. could be easily produced in our laboratories simply by replacing cold nutrients (like glucose for DNA/RNA labelling, or amino acids for protein labelling) with 14C-labelled versions. Of course, our laboratories are equipped with an ACTA to purify a product to specifications after production. We have a track record in biodistribution and off target binding investigations.