Fit-For-Purpose Hepatocyte Models Enable the Identification of Early Events Contributing to Idelalisib-Induced Liver Injury

Abstract

Introduction:

Idelalisib is a phosphatidylinositol 3-delta kinase inhibitor that has shown good efficacy in treating some hematologic malignancies. Rare, but potentially serious liver toxicity was associated with idelalisib use in clinical trials. The objective of this study was to evaluate the early idelalisib-induced changes in human hepatocytes using a combination of in vitro models and techniques to identify mechanisms contributing to overt liver injury observed in the clinic.

Materials and Methods:

Primary human hepatocytes from two donors and the HepaRG cell line were cultured as three-dimensional (3D) liver models, with and without primary human nonparenchymal cells. A panel of high-content imaging endpoints was used to evaluate responses across six concentrations of idelalisib (0.6–180 μM) and three timepoints of exposure (1, 7, and 14 days). Primary human hepatocytes from three donors were also sandwich cultured in two-dimensional (2D) format and assayed for cytotoxicity, global gene expression, and exosome responses across similar concentrations of idelalisib after a 1-day exposure.

Results:

In 3D liver models, the most sensitive endpoints to idelalisib were ATP and glutathione depletion and longer exposures resulted in a more robust response. In 2D hepatocytes, statistically significant decreases in albumin secretion were observed at both the 60 and 180 μM concentrations and the most significantly enriched pathway among genes upregulated in response to idelalisib was “Endoplasmic Reticulum Stress.”

Discussion and Conclusion:

Taken together, these data suggest that oxidative stress is an early event contributing to idelalisib-induced liver injury and demonstrate how fit-for-purpose in vitro models can be used to investigate mechanisms of drug toxicity.