Cell Toxicity Models
Liver toxicity is a major cause of clinical trial failures and has played a significant role in the withdrawl of several drugs from the market. Evaluation of toxicity is performed throughout the drug development pipeline. However, for liver toxicity in particular, the models for detection early in the pipeline which are mostly animal-based fall short of meeting expectations. Increasingly, in vitro human models are being explored as an alternative in or to augment findings in animal models as a means to improve preclinical prediction of liver toxicity.
Building Complex Liver Toxicity Models
The ability now to create in vitro models that co-culture hepatocytes with Kupffer cells, the liver resident macrophage, can improve the ability to detect these complex toxicities early in development. Other new models such as co-cultures with stellate and liver endothelial cells, in both monolayer and 3D spheroid models, have been shown to increase the predictive power of cell culture models (9).
Humanized Mouse Models
An immunocompromised mouse model can be made to house a liver composed almost entirely of human liver cells. The purpose of creating such a model is to enable human-relevant liver pharmacokinetics and pharmacodynamics studies to be performed in an intact mouse model.These models can be used to re-create human specific liver toxicities in an in vivo environment, but are also used for modeling infectious diseases that impact the human liver. Hepatocytes used for making humanized mouse models should be plateable and of high quality, but don’t necessarily need to be prequalified for drug-drug interaction studies. Lonza therefore recommends Human Cryopreserved Hepatocytes, Plateable, General Purpose cells (HUCPG).
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