Predicting drug-induced liver toxicity remains a critical, yet elusive, goal in drug safety studies and drug development. This difficulty is a result of the often weak relationship between in vitro and animal toxicity models, as well as between animal models and human toxicity. To address this gap in drug development, we have employed a high-throughput, three-dimensional cell culture platform containing human and murine primary hepatocytes, and human and murine transformed hepatoma cell lines, to screen a library of 27 small molecule drugs of various mechanisms of action and modes of toxicity. Correlations of in vitro toxicity (as represented by IC50 values) to in vivo mouse toxicity (LD50 values) suggest that this system is mildly representative of in vivo toxicity results. To enhance these in vitro-in vivo correlations, we exploited a humanized mouse model wherein the same human hepatocytes used for in vitro studies were engrafted into TK-NOG mice and in vivo liver toxicity evaluated on a subset of compounds. This humanized mouse model provides highly comprehensive in vitro-in vivo correlations as a result of using identical human hepatocytes in both the in vitro and in vivo systems. In turn, this approach has promise in advancing earlier-stage drug safety assessment with greater predictive value.

Liver toxicity comparisons of small molecule drugs in a high-throughput 3D In vitro culture system and in humanized liver mice

255th National Meeting (2018)

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