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Review
. 2016;2016:9737920.
doi: 10.1155/2016/9737920. Epub 2016 Sep 5.

Key Challenges and Opportunities Associated With the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

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Free PMC article
Review

Key Challenges and Opportunities Associated With the Use of In Vitro Models to Detect Human DILI: Integrated Risk Assessment and Mitigation Plans

Franck A Atienzar et al. Biomed Res Int. .
Free PMC article

Abstract

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.

Figures

Figure 1
Figure 1
Overview of mechanisms of DILI. Figure extracted from Godoy et al. [21]. (1) Detoxification: conjugation with glutathione. (2) Altered calcium homeostasis. (3) Reactive metabolites may bind to transport pumps or actin around the bile canaliculi preventing bile export. (4) Reactive metabolites binding to mitochondrial proteins may reduce ATP formation, produce ROS, and open the MPTP causing apoptosis. (5) Immune stimulation via the hapten or prohapten mechanisms leading to either humoral (B cell) or cell-mediated (T cell) reactions. (6) Immune activation (PI mechanism with parent drug). (7) TNF receptor sensitivity may be heightened increasing responsiveness to TNF, leading to apoptosis. For more details, please refer to Godoy et al. [21]. Figure reproduced with permission.
Figure 2
Figure 2
The schema to refine the drug labeling based DILI annotations by weighting the causality evidence. Three verified categories (vMost-, vLess-, and vNo-DILI-concern) and one “Ambiguous DILI-concern” group were classified in the new schema. For more details, please refer to Chen et al. [65]. Figure reproduced with permission.
Figure 3
Figure 3
HCI assay examples for assessment of specific cellular functions and toxicity. For more details, please refer to Uteng et al. [81]. Figure reproduced with permission.

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