Category: Preclinical Development
Purpose: Drug-induced liver injury (DILI) is one of the primary challenges for drug development in part because of the limited success with existing preclinical models. This concern has led to significant efforts in evaluating alternative methods, particularly animal-free approaches, for predicting DILI in humans. Most of these methods are high throughput and capable of screening many chemicals in a relatively short period. A large drug list with known DILI severity and toxicity facilitates identification of molecular features, cellular responses and risk factors that distinguish DILI positives from negatives.
Methods: Previously, we reported DILIrank that consisted of 775 drugs and their DILI classifications, assessed using FDA approved drug labeling information (Chen et al, Drug Discovery Today, 21(4):648-53, 2016). In this study, we augmented DILIrank with four large literature datasets (N >350 drugs) using a statistical approach to generate DILIst (DILI severity and toxicity).
Results: The augmentation was carried out separately for each DILI class (i.e., positive or negative) and resulted in a DILIst database of 1303 drugs of which 789 were DILI positives (increased 69% from DILIrank) and 514 were DILI negatives (increased by 66%). Using the Anatomical Therapeutic Chemical (ATC) classification system, DILIst covered 14 anatomical categories (five of which had >100 drugs), 172 pharmacological subgroups (including 16 subgroups not represented in DILIrank) and 381 chemical subgroups (including 66 subgroups not represented in DILIrank).
Conclusion: DILIst provides access to the most significant number of drugs classified by human hepatotoxicity with the broadest coverage of drug classes to date. DILIst is an invaluable resource for the community to improve DILI research in the areas of elucidation of mechanisms, predictive model development, and biomarker identification, and provides additional opportunities to exploit the potential of emerging technologies.
Shraddha Thakkar– Principal Investigator , National Center of Toxicological Research/ US FDA, Jefferson, Arkansas
Ting Li– Jefferson, Arkansas
Zhichao Liu– Principal Investigator , NCTR/FDA, Jefferson, Arkansas
Ruth Roberts– Director, ApconiX, Cheshire, England, United Kingdom
Weida Tong– Division Director, Division of Bioinformatics Biostatistics, NCTR, US Food and Drug Administration, Jefferson, Arkansas