Comprehensive Evaluation of Organotypic and Microphysiological Liver Models for Prediction of Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) is a major concern for the pharmaceutical industry and constitutes one of the most important reasons for the termination of promising drug development projects. Reliable prediction of DILI liability in preclinical stages is difficult, as current experimental model systems do not accurately reflect the molecular phenotype and functionality of the human liver. As a result, multiple drugs that passed preclinical safety evaluations failed due to liver toxicity in clinical trials or postmarketing stages in recent years. To improve the selection of molecules that are taken forward into the clinics, the development of more predictive in vitro systems that enable high-throughput screening of hepatotoxic liabilities and allow for investigative studies into DILI mechanisms has gained growing interest. Specifically, it became increasingly clear that the choice of cell types and culture method both constitute important parameters that affect the predictive power of test systems. In this review, we present current 3D culture paradigms for hepatotoxicity tests and critically evaluate their utility and performance for DILI prediction. In addition, we highlight possibilities of these emerging platforms for mechanistic evaluations of selected drug candidates and present current research directions towards the further improvement of preclinical liver safety tests. We conclude that organotypic and microphysiological liver systems have provided an important step towards more reliable DILI prediction. Furthermore, we expect that the increasing availability of comprehensive benchmarking studies will facilitate model dissemination that might eventually result in their regulatory acceptance.

Scalable Biomimetic Coaxial Aligned Nanofiber Cardiac Patch: A Potential Model for “Clinical Trials in a Dish”

“…Overall, these results strongly indicated an elevated sensitivity of hiPSC-CMs in 3D cultures to various drugs used in this study. Similar observations were reported in the case of 3D culture of primary hepatocytes (Bell et al, 2018;Zhou et al, 2019) and cancer cells (Chaicharoenaudomrung et al, 2019). Likewise, a recent study demonstrated that 3D cardiac spheroids mimics an in vivo environment for drug testing and cardiotoxicity studies (Polonchuk et al, 2017).…”

Detection of acute toxicity of aflatoxin B1 to human hepatocytes in vitro and in vivo using chimeric mice with humanized livers

“…In general, it is difficult to detect the hepatotoxicity of test compounds, which require bioactivation by metabolic enzymes with a long-term exposure at a low dose, with lack of toxicity in short-term treatment. Even though primary HHs are considered a gold standard for in vitro toxicity study, many hepatocyte characteristics, including CYP activity, quickly diminish in vitro [ 37 ]. However, in terms of CYP3A activity, PXB-cells exhibited comparable CYP3A activity to freshly isolated or cryopreserved primary HHs, at least until 3 weeks after plating, as previously reported [ 27 ].…”

Current Advances on 3D‐Bioprinted Liver Tissue Models

“…3D‐bioprinted liver tissue models are a powerful tool for testing the hepatotoxicity of drug candidates during drug screening. [ 45 ] Nguyen et al. 3D‐bioprinted defined liver tissue constructs with patient‐derived hepatocytes and nonparenchymal cells and assessed the organ‐level response to clinical drug‐induced hepatotoxicity.…”