Increase clinical translation with Organ-Chips for ADME-Tox assessments
Accurate ADME-Tox profiling of preclinical drug candidates remains a challenge
Preclinical ADME-Tox (Absorption, Distribution, Metabolism, Excretion, and Toxicity) studies are pivotal to predicting human response. However, approximately 30% of drugs fail during human clinical trials due to adverse reactions despite promising preclinical study results, and another 60% fail due to lack of efficacy. As companies broaden the modality toolbox with novel drug delivery mechanisms, clinical translation becomes even more challenging. Put simply, current models do not offer the predictive value required to confidently transition drug candidates to the clinic.
How we can help
Translate to the clinic with confidence
Organ-on-a-Chip technology enables researchers to evaluate the ADME-Tox profile of preclinical drug candidates in advanced in vitro models that more closely emulate human response. Human-based cell sourcing reduces species translation issues seen in animal models, while the organ-specific microenvironment and mechanical forces induced by flow and stretch improve performance over conventional cell culture. These factors result in more physiologically relevant models of various organs—including the liver, kidney, and intestine—that can have higher predictive validity in modeling clinical outcomes.
Clinically predictive toxicity assessment with Organ-Chips
An analysis of 150 drug candidates that caused adverse events in humans demonstrated that testing in rats and dogs only predicted 71% of human toxicities. The liver is of particular concern, as drug-induced liver injury (DILI) is the primary cause for withdrawal of drugs from the market and throughout drug development. Organ-on-a-Chip technology can enable researchers to predict diverse mechanisms of drug toxicity, assess the human relevance of toxicity observed in animals, and translate mechanisms of toxicity for candidates with unexpected safety signals in the clinic.
Assessment of drug metabolism with human Organ-Chips
Animal studies are often used to study the metabolism and toxicity of drug candidates. However, species differences in drug metabolism, including isoform composition, expression, and catalytic enzyme activity can lead to large differences in substrate specificity and catalytic activity, limiting understanding of how humans will response to the drug candidate.
A study published in Science Translational Medicine showcases how species-specific versions of the Liver-Chip can be used to identify differences in drug metabolism and toxicity. The study revealed that CYP activities measured in the co-culture human, rat, and dog chips over a 14-day culture period were comparable to, or in some cases greater than, those exhibited by freshly isolated hepatocytes.
How Organ-Chips are being used
In collaboration with pharmaceutical companies, researchers used Liver-Chip to investigate diverse mechanisms of toxicity and assess species differences. First, by administering bosentan to species-specific rat, dog, and human Liver-Chips, researchers successfully recreated species differences observed in vivo, with cholestasis only occurring in the human Liver-Chip.
Researchers also administered a range of drug compounds to a quad-culture configuration of the Liver-Chip. These studies were able to detect Kupffer cell depletion as well as markers of steatosis and fibrosis, demonstrating how Organ-Chips can be used to investigate a variety of toxicity mechanisms.
Lastly, the Liver-Chip was used to study the toxicity of TAK-875, a drug candidate discontinued during phase III trials due to DILI in a few individuals. Results showed that prolonged exposure caused mitochondrial dysfunction, oxidative stress, lipid droplet formation, and an innate immune response, all harbingers of DILI for susceptible patients. Taken together, this shows the potential to use the Organ-Chips to assess human-specific toxicity concerns that conventional preclinical models fail to recapitulate.
A range of Organ-Chip models to study drug ADME-Tox profiles in a human-relevant system
During preclinical drug development, Organ-on-a-Chip technology can be used to study the ADME-Tox profiles of drug candidates in validated models of the liver, kidney, and intestine.
Primary human cell models reduce species differences
Microenvironment and mechanical forces improve gene expression
Investigate diverse mechanisms of toxicity
Study drug metabolism in a human-based model
Supported Organ Models
Study drug absorption and drug-drug interactions in a primary organoid-based model of the human small intestine.
Investigate mechanisms of toxicity for preclinical drug candidates to help decrease clinical trial safety failures.
Evaluate drug candidate toxicity at clinically-relevant concentrations in a co-culture human kidney model.