Control compounds for preclinical drug-induced liver injury assessment: Consensus-driven systematic review by the ProEuroDILI network.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by drugs, and herbal or dietary supplements. Early identification of human hepatotoxicity at preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. In this systematic review, we analyzed the compounds used in hepatotoxicity assays and established a list of DILI-positive and -negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by an expert committee from the COST Action ProEuroDILI Network (CA17112). METHODS: Following 2020 PRISMA guidelines, original research articles focusing on DILI which used in vitro human models and performed at least one hepatotoxicity assay with positive and negative control compounds, were included. Bias of the studies was assessed by a modified 'Toxicological Data Reliability Assessment Tool'. RESULTS: A total of 51 studies (out of 2,936) met the inclusion criteria, with 30 categorized as reliable without restrictions. Although there was a broad consensus on positive compounds, the selection of negative compounds lacked clarity. 2D monoculture, short exposure times and cytotoxicity endpoints were the most tested, although there was no consensus on drug concentrations. CONCLUSIONS: Extensive analysis highlighted the lack of agreement on control compounds for in vitro DILI assessment. Following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative control drugs for validation of in vitro models of DILI is proposed. IMPACT AND IMPLICATIONS: Prediction of human toxicity early in the drug development process remains a major challenge, necessitating the development of more physiologically relevant liver models and careful selection of drug-induced liver injury (DILI)-positive and -negative control drugs to better predict the risk of DILI associated with new drug candidates. Thus, this systematic study has crucial implications for standardizing the validation of new in vitro models of DILI. By establishing a consensus-driven list of positive and negative control drugs, the study provides a scientifically justified framework for enhancing the consistency of preclinical testing, thereby addressing a significant challenge in early hepatotoxicity identification. Practically, these findings can guide researchers in evaluating safety profiles of new drugs, refining in vitro models, and informing regulatory agencies on potential improvements to regulatory guidelines, ensuring a more systematic and efficient approach to drug safety assessment.

Methods for causality assessment of idiosyncratic drug-induced liver injury.

The diagnosis of idiosyncratic drug-induced liver injury (DILI) is a challenging task due to the lack of specific features or definitive diagnostic tools. A minimum of clinical and pharmacological information is required, together with laboratory and imaging tests to exclude other causes of liver injury. Several standardized methods have been developed to support clinical judgement and establish causality assessment, the most widely used being the Roussel Uclaf Causality Assessment Method-RUCAM-and structured Expert Opinion. More recently, an evidence-based, revised RUCAM, Electronic Causality Assessment Method-RECAM-has been developed and, although still a work in progress, may replace RUCAM scoring in the future. International collaborative networks and ongoing research efforts are key to advancing biomarker qualification and validation and developing new in vitro patient-based methods that will help improve DILI diagnosis and move towards a personalized medicine approach.

Clinical presentation, causative drugs and outcome of patients with autoimmune features in two prospective DILI registries.

BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (DILI) with autoimmune features is a liver condition with laboratory and histological characteristics similar to those of idiopathic autoimmune hepatitis (AIH), which despite being increasingly reported, remains largely undefined. We aimed to describe in-depth the features of this entity in a large series of patients from two prospective DILI registries. METHODS: DILI cases with autoimmune features collected in the Spanish DILI Registry and the Latin American DILI Network were compared with DILI patients without autoimmune features and with an independent cohort of patients with AIH. RESULTS: Out of 1,426 patients with DILI, 33 cases with autoimmune features were identified. Female sex was more frequent in AIH patients than in the other groups (p = .001). DILI cases with autoimmune features had significantly longer time to onset (p < .001) and resolution time (p = .004) than those without autoimmune features. Interestingly, DILI patients with autoimmune features who relapsed exhibited significantly higher total bilirubin and transaminases at onset and absence of peripheral eosinophilia than those who did not relapse. The likelihood of relapse increased over time, from 17% at 6 months to 50% 4 years after biochemical normalization. Statins, nitrofurantoin and minocycline were the drugs most frequently associated with this phenotype. CONCLUSIONS: DILI with autoimmune features shows different clinical features than DILI patients lacking characteristics of autoimmunity. Higher transaminases and total bilirubin values with no eosinophilia at presentation increase the likelihood of relapse in DILI with autoimmune features. As the tendency to relapse increases over time, these patients will require long-term follow-up.

Modeling drug-induced liver injury: current status and future prospects.

INTRODUCTION: Idiosyncratic drug-induced liver injury (iDILI) is a challenging and unpredictable multifactorial condition. At present, validated preclinical models for the prediction of the hepatotoxic potential of a given drug are scarce. AREAS COVERED: This review intends to sum up the current knowledge about in vitro (including hepatocyte 2D cultures, cocultures with non-parenchymal cells, 3D configurations and non-typical closer to reality in vitro models), in vivo (covering models for immunological and oxidative stress features, humanized mouse-based and non-rodent models) and in silico approaches for iDILI modeling, highlighting the recent advances in each topic. EXPERT OPINION: The future strategy for iDILI modeling should be patient-centered. Future animal and cell-based models, with more predictive value, will be easier to design by using a more translational approach based on mechanisms demonstrated in humans. Genetic and epigenetic information gathered from iDILI patients, together with data from in vitro and in vivo studies, could be used to develop sophisticated predictive in silico models to find compounds with iDILI potential. Collecting genetic, metabolic, and biomarker data from patient cohorts might be another option to create a 'fingerprint' characteristic of people at risk, allowing for the development of new, mechanistic strategies to enhance iDILI in vitro evaluation.