The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.
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ABSTRACT:
SUBMITTER: Walker PA
PROVIDER: S-EPMC7395068 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
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The evolution of strategies to minimise the risk of human drug-induced liver injury (DILI) in drug discovery and development.
Walker Paul A PA Ryder Stephanie S Lavado Andrea A Dilworth Clive C Riley Robert J RJ
Archives of toxicology 20200506 8
Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with mult ...[more]
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Project description:Drug-induced liver injury (DILI) is an adverse toxic hepatic clinical reaction associated to the administration of a drug that can occur both at early clinical stages of drug development, as well after normal clinical usage of approved drugs. Because of its unpredictability and clinical relevance, it is of medical concern. Three DILI phenotypes (hepatocellular, cholestatic, and mixed) are currently recognized, based on serum alanine aminotransferase (ALT) and alkaline phosphatase (ALP) values. However, this classification lacks accuracy to distinguish among the many intermediate mixed types, or even to estimate the magnitude and progression of the injury. It was found desirable to have additional elements for better evaluation criteria of DILI. With this aim, we have examined the serum metabolomic changes occurring in 79 DILI patients recruited and monitored using established clinical criteria, along the course of the disease and until recovery. Results revealed that free and conjugated bile acids, and glycerophospholipids were among the most relevant metabolite classes for DILI phenotype characterization. Using an ensemble of PLS-DA models, metabolomic information was integrated into a ternary diagram to display the disease phenotype, the severity of the liver damage, and its progression. The modeling implemented and the use of such compiled information in an easily understandable and visual manner facilitates a straightforward DILI phenotyping and allow to monitor its progression and recovery prediction, usefully complementing the concise information drawn out by the ALT and ALP classification.
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Project description:Drug-induced liver injury (DILI) is one the most unpredictable adverse reactions to xenobiotics in humans and the leading cause of postmarketing withdrawals of approved drugs. To date, these drugs have been collated by the FDA to form the DILIRank database, which classifies DILI severity and potential. These classifications have been used by various research groups in generating computational predictions for this type of liver injury. Recently, groups from Pfizer and AstraZeneca have collated DILI in vitro data and physicochemical properties for compounds that can be used along with data from the FDA to build machine learning models for DILI. In this study, we have used these data sets, as well as the Biopharmaceutics Drug Disposition Classification System data set, to generate Bayesian machine learning models with our in-house software, Assay Central. The performance of all machine learning models was assessed through both the internal 5-fold cross-validation metrics and prediction accuracy of an external test set of compounds with known hepatotoxicity. The best-performing Bayesian model was based on the DILI-concern category from the DILIRank database with an ROC of 0.814, a sensitivity of 0.741, a specificity of 0.755, and an accuracy of 0.746. A comparison of alternative machine learning algorithms, such as k-nearest neighbors, support vector classification, AdaBoosted decision trees, and deep learning methods, produced similar statistics to those generated with the Bayesian algorithm in Assay Central. This study demonstrates machine learning models grouped in a tool called MegaTox that can be used to predict early-stage clinical compounds, as well as recent FDA-approved drugs, to identify potential DILI.
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Project description:Drug-induced liver injury (DILI) is one of the most frequent adverse clinical reactions and a relevant cause of morbidity and mortality. Hepatotoxicity is among the major reasons for drug withdrawal during post-market and late development stages, representing a major concern to the pharmaceutical industry. The current biochemical parameters for the detection of DILI are based on enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP)) and bilirubin serum levels that are not specific of DILI and therefore there is an increasing interest on novel, specific, DILI biomarkers discovery. Metabolomics has emerged as a tool with a great potential for biomarker discovery, especially in disease diagnosis, and assessment of drug toxicity or efficacy. This review summarizes the multistep approaches in DILI biomarker research and discovery based on metabolomics and the principal outcomes from the research performed in this field. For that purpose, we have reviewed the recent scientific literature from PubMed, Web of Science, EMBASE, and PubTator using the terms "metabolomics", "DILI", and "humans". Despite the undoubted contribution of metabolomics to our understanding of the underlying mechanisms of DILI and the identification of promising novel metabolite biomarkers, there are still some inconsistencies and limitations that hinder the translation of these research findings into general clinical practice, probably due to the variability of the methods used as well to the different mechanisms elicited by the DILI causing agent.
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Project description:Causality assessment for suspected drug-induced liver injury (DILI) during drug development and following approval is challenging. The IQ DILI Causality Working Group (CWG), in collaboration with academic and regulatory subject matter experts (SMEs), developed this manuscript with the following objectives: (1) understand and describe current practices; (2) evaluate the utility of new tools/methods/practice guidelines; (3) propose a minimal data set needed to assess causality; (4) define best practices; and (5) promote a more structured and universal approach to DILI causality assessment for clinical development. To better understand current practices, the CWG performed a literature review, took a survey of member companies, and collaborated with SMEs. Areas of focus included best practices for causality assessment during clinical development, utility of adjudication committees, and proposals for potential new avenues to improve causality assessment. The survey and literature review provided renewed understanding of the complexity and challenges of DILI causality assessment as well as the use of non-standardized approaches. Potential areas identified for consistency and standardization included role and membership of adjudication committees, standardized minimum dataset, updated assessment tools, and best practices for liver biopsy and rechallenge in the setting of DILI. Adjudication committees comprised of SMEs (i.e., utilizing expert opinion) remain the standard for DILI causality assessment. A variety of working groups continue to make progress in pursuing new tools to assist with DILI causality assessment. The minimum dataset deemed adequate for causality assessment provides a path forward for standardization of data collection in the setting of DILI. Continued progress is necessary to optimize and advance innovative tools necessary for the scientific, pharmaceutical, and regulatory community.
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Project description:BackgroundDrug-induced liver injury (DILI) requires accurate case adjudication, with expert opinion being the current best practice.AimWe utilised a novel DILI causality assessment tool (DILI-CAT), which uses drug-specific liver injury phenotypes, to examine potential DILI in early phase ximelagatran clinical development.MethodsWe conducted a retrospective analysis of liver injury events from four Stroke Prevention using an ORal Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) trials, in which patients were randomised to receive oral ximelagatran or adjusted-dose warfarin. A stepwise process was used with iterative adjustments. The DILI phenotype was characterised by latency, R-value, and AST/ALT ratio. A scoring algorithm was applied to liver events to assess how closely the liver events matched the Interquatile-Range for the working phenotype for each of the three parameters.FindingsData from 3115 patients included in the SPORTIF trials as above were available. The initial ximelagatran phenotype was developed based on five liver injury cases from the ximelagatran arm and was then validated against an additional eight cases (5 ximelagatran, 3 warfarin); in these eight cases, there was a statistically significant difference in the total DILI-CAT scores of the two drugs (p = 0.016) between ximelagatran and warfarin. Together, these ten ximelagatran cases generated a second, refined ximelagatran phenotype, which was validated against an additional 75 cases (53 ximelagatran/22 warfarin)-again with statistically significant different DILI-CAT ximelagatran vs. warfarin scores (p < 0.001).ConclusionDILI-CAT, a clinically intuitive, data-driven, computer-assisted scoring algorithm, is a useful tool for early detection of drug's hepatotoxicity in clinical drug development.
| S-EPMC9164935 | biostudies-literature
Project description:BackgroundDrug-induced liver injury (DILI) is a major safety concern characterized by a complex and diverse pathogenesis. In order to identify DILI early in drug development, a better understanding of the injury and models with better predictivity are urgently needed. One approach in this regard are in silico models which aim at predicting the risk of DILI based on the compound structure. However, these models do not yet show sufficient predictive performance or interpretability to be useful for decision making by themselves, the former partially stemming from the underlying problem of labeling the in vivo DILI risk of compounds in a meaningful way for generating machine learning models.ResultsAs part of the Critical Assessment of Massive Data Analysis (CAMDA) "CMap Drug Safety Challenge" 2019 ( http://camda2019.bioinf.jku.at ), chemical structure-based models were generated using the binarized DILIrank annotations. Support Vector Machine (SVM) and Random Forest (RF) classifiers showed comparable performance to previously published models with a mean balanced accuracy over models generated using 5-fold LOCO-CV inside a 10-fold training scheme of 0.759 ± 0.027 when predicting an external test set. In the models which used predicted protein targets as compound descriptors, we identified the most information-rich proteins which agreed with the mechanisms of action and toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs), one of the most important drug classes causing DILI, stress response via TP53 and biotransformation. In addition, we identified multiple proteins involved in xenobiotic metabolism which could be novel DILI-related off-targets, such as CLK1 and DYRK2. Moreover, we derived potential structural alerts for DILI with high precision, including furan and hydrazine derivatives; however, all derived alerts were present in approved drugs and were over specific indicating the need to consider quantitative variables such as dose.ConclusionUsing chemical structure-based descriptors such as structural fingerprints and predicted protein targets, DILI prediction models were built with a predictive performance comparable to previous literature. In addition, we derived insights on proteins and pathways statistically (and potentially causally) linked to DILI from these models and inferred new structural alerts related to this adverse endpoint.
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Project description:Drug discovery is a costly process which usually takes more than 10 years and billions of dollars for one successful drug to enter the market. Despite all the safety tests, drugs may still cause adverse reactions and be restricted in use or even withdrawn from the market. Drug-induced liver injury (DILI) is one of the major adverse drug reactions, and computational models may be used to predict and reduce it. To assess the computational prediction performance of DILI, we curated DILI endpoints from three databases and prepared drug features including chemical descriptors, therapeutic classifications, gene expressions, and binding proteins. We trained machine-learning models to predict the various DILI endpoints using different drug features. Using the optimal feature sets, the top-performing models obtained areas under the receiver operating characteristic curve (AUC) around 0.8 for some DILI endpoints. We found that some features, including therapeutic classifications and proteins, have good prediction performance towards DILI. We also discovered that the severity of DILI endpoints as well as the selection of negative samples may significantly affect the prediction results. Overall, our study provided a comprehensive collection, curation, and prediction of DILI endpoints using various drug features, which may help the drug researchers to better understand and prevent DILI during the drug discovery process.
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Project description:Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts-neoantigens-that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.
| S-EPMC8000729 | biostudies-literature
Project description:Discovery proteomics was conducted on serum samples using tandem mass tagging for relative quantitation to discover potential new biomarkers of DILI.
2022-07-01 | MSV000089782 | MassIVE
Project description:There is a clear need for better biomarkers of drug-induced-liver-injury (DILI).We aimed to evaluate the possible prognostic value of ActiTest and FibroTest proteins apoliprotein-A1, haptoglobin and alpha-2-macroglobulin, in patients with DILI.We analyzed cases and controls included in the IMI-SAFE-T-DILI European project, from which serum samples had been stored in a dedicated biobank. The analyses of ActiTest and FibroTest had been prospectively scheduled. The primary objective was to analyze the performance (AUROC) of ActiTest components as predictors of recovery outcome defined as an ALT <2x the upper limit of normal (ULN), and BILI <2x ULN.After adjudication, 154 patients were considered to have DILI and 22 were considered to have acute liver injury without DILI. A multivariate regression analysis (ActiTest-DILI patent pending) combining the ActiTest components without BILI and ALT (used as references), apolipoprotein-A1, haptoglobin, alpha-2-macroglobulin and GGT, age and gender, resulted in a significant prediction of recovery with 67.0% accuracy (77/115) and an AUROC of 0.724 (P<0.001 vs. no prediction 0.500). Repeated apolipoprotein-A1 and haptoglobin remained significantly higher in the DILI cases that recovered (n = 65) versus those that did not (n = 16), at inclusion, at 4-8 weeks and at 8-12 weeks. The same results were observed after stratification on APAP cases and non-APAP cases.We identified that apolipoprotein-A1 and haptoglobin had significant predictive values for the prediction of recovery at 12 weeks in DILI, enabling the construction of a new prognostic panel, the DILI-ActiTest, which needs to be independently validated.
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