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Updated: Mar 14, 2026
Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
Published on: January 31, 2022
Key Challenges and Opportunities Associated with the Use of In Vitro Models to Detect Human DILI: Integrated Risk
Franck A Atienzar1, Eric A Blomme2, Minjun Chen3
1UCB BioPharma SPRL, Chemin du Foriest, R9 Building, 1420 Braine-l'Alleud, Belgium.
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.
Insights
Predicting drug-induced liver injury (DILI) remains challenging, especially idiosyncratic DILI (iDILI). Improved preclinical models and integrated risk assessment are crucial for better drug safety and development.
Area of Science:
- Toxicology
- Pharmacology
- Drug Development
Background:
- Drug-induced liver injury (DILI) is a significant barrier in drug development, causing attrition, withdrawal, and acute liver failure.
- Despite decades of research, predicting DILI, particularly idiosyncratic DILI (iDILI), remains difficult due to unclear mechanisms and multifactorial causes.
- Current preclinical models for DILI prediction require improvement, highlighting the need for novel test systems and better harmonization.
Approach:
- This paper reviews key challenges in interpreting DILI data, practical considerations, and limitations of current models.
- It emphasizes the necessity of an integrated risk assessment approach for predicting DILI.
- The authors discuss opportunities for improvement through harmonization of in vitro systems and implementation strategies for preclinical DILI models.
Key Points:
- Predicting intrinsic DILI has improved, but idiosyncratic DILI (iDILI) prediction remains a major hurdle.
- Lack of clear mechanistic understanding and defined clinical criteria hinder iDILI risk assessment.
- Harmonization of in vitro systems, adoption of newer technologies, and precompetitive consortia can enhance DILI prediction.
Conclusions:
- Improving DILI prediction requires concerted efforts in harmonizing existing and emerging in vitro systems.
- Implementing standardized preclinical DILI models across the pharmaceutical industry is essential.
- Adopting novel technologies and fostering collaboration through precompetitive consortia offer promising avenues for advancing drug safety evaluation.
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