Prediction of hepatic drug clearance with a human microfluidic four-cell liver acinus microphysiology system

Abstract

Predicting human hepatic clearance remains a fundamental challenge in both pharmaceutical drug development and toxicological assessments of environmental chemicals, with concerns about both accuracy and precision of in vitro-derived estimates. Suggested sources of these issues have included differences in experimental protocols, differences in cell sourcing, and use of a single cell type, liver parenchymal cells (hepatocytes). Here we investigate the ability of human microfluidic four-cell liver acinus microphysiology system (LAMPS) to make predictions as to hepatic clearance for seven representative compounds: Caffeine, Pioglitazone, Rosiglitazone, Terfenadine, Tolcapone, Troglitazone, and Trovafloxacin. The model, whose reproducibility was recently confirmed in an inter-lab comparison, was constructed using primary human hepatocytes or human induced pluripotent stem cell (iPSC)-derived hepatocytes and 3 human cell lines for the endothelial, Kupffer and stellate cells. We calculated hepatic clearance estimates derived from experiments using LAMPS or traditional 2D cultures and compared the outcomes with both in vivo human clinical study-derived and in vitro human hepatocyte suspension culture-derived values reported in the literature. We found that, compared to in vivo clinically-derived values, the LAMPS model with iPSC-derived hepatocytes had higher precision as compared to primary cells in suspension or 2D culture, but, consistent with previous studies in other microphysiological systems, tended to underestimate in vivo clearance. Overall, these results suggest that use of LAMPS and iPSC-derived hepatocytes together with an empirical scaling factor warrants additional study with a larger set of compounds, as it has the potential to provide more accurate and precise estimates of hepatic clearance.