In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs

Thompson, Richard A.; Isin, Emre M.; Li, Yan; Weidolf, Lars; Page, Ken; Wilson, Ian D.; Swallow, Steve; Middleton, Brian; Stahl, Simone; Foster, Alison J.; Dolgos, Hugues; Weaver, Richard J.; Kenna, J. Gerry

doi:10.1021/tx300091x

Cited by 195 publications

(218 citation statements)

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“…The performance of HCS assays could be further improved by incorporating other liver relevant endpoints, such as reactive oxygen species, glutathione depletion, and inhibition of bile salt export pumps (Stepan et al 2011;Thompson et al 2012). These mechanistic endpoints are expected to supplement the prelethal endpoints employed in this study.…”

Section: Discussionmentioning

confidence: 99%

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model

et al. 2014

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Drug-induced liver injury (DILI) is a major cause of drug failures in both the preclinical and clinical phase. Consequently, improving prediction of DILI at an early stage of drug discovery will Correspondence to: Weida Tong. Jürgen Borlak and Weida Tong have contributed equally to the manuscript.Disclaimer: The views presented in this article do not necessarily reflect current or future opinion or policy of the US Food and Drug Administration. Any mention of commercial products is for clarification and not intended as endorsement. Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-014-1276-9) contains supplementary material, which is available to authorized users. HHS Public AccessAuthor manuscript Arch Toxicol. Author manuscript; available in PMC 2018 January 04.Published in final edited form as:Arch Toxicol. 2014 July ; 88(7): 1439-1449. doi:10.1007/s00204-014-1276-9. Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript reduce the potential failures in the subsequent drug development program. In this regard, highcontent screening (HCS) assays are considered as a promising strategy for the study of DILI; however, the predictive performance of HCS assays is frequently insufficient. In the present study, a new testing strategy was developed to improve DILI prediction by employing in vitro assays that was combined with the RO2 model (i.e., 'rule-of-two' defined by daily dose ≥100 mg/day & logP ≥3). The RO2 model was derived from the observation that high daily doses and lipophilicity of an oral medication were associated with significant DILI risk in humans. In the developed testing strategy, the RO2 model was used for the rational selection of candidates for HCS assays, and only the negatives predicted by the RO2 model were further investigated by HCS. Subsequently, the effects of drug treatment on cell loss, nuclear size, DNA damage/fragmentation, apoptosis, lysosomal mass, mitochondrial membrane potential, and steatosis were studied in cultures of primary rat hepatocytes. Using a set of 70 drugs with clear evidence of clinically relevant DILI, the testing strategy improved the accuracies by 10 % and reduced the number of drugs requiring experimental assessment by approximately 20 %, as compared to the HCS assay alone. Moreover, the testing strategy was further validated by including published data (Cosgrove et al. in Toxicol Appl Pharmacol 237:317-330, 2009) on drug-cytokine-induced hepatotoxicity, which improved the accuracies by 7 %. Taken collectively, the proposed testing strategy can significantly improve the prediction of in vitro assays for detecting DILI liability in an early drug discovery phase.

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Section: Discussionmentioning

confidence: 99%

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model

et al. 2014

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“…Other serious adverse events include acute renal injury, heart failure, adverse reproductive outcomes [78] and liver injury [79]. Diclofenac is the most frequently reported NSAID showing side effects predominantly related to hepatocellular (centrilobular), mixed and cholestatic type of liver injury, which leads to liver failure [80]. Diclofenac liver toxicity in humans is idiosyncratic [81], and although various mechanisms for diclofenac-induced liver injury have been proposed, none have been fully understood.…”

Section: Diclofenac Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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“…This makes the in vitro assay highly valuable as it is able to identify compounds with risk of inducing cholestasis (table 1), which are not identified by routine toxicity testing in animals, and can therefore be used to predict DILI [15,17]. It has been proposed to combine data on transporter inhibition with cytotoxicity and covalent binding data, as an integrated approach to assess the risk of hepatotoxicity [22]. During the drug discovery phase at Lundbeck, the bile salt transporter inhibition assays are performed as second-tier assays on the most interesting compounds from projects and chemicals series, using HCS on primary hepatocytes of either rat or human origin.…”

Section: Bile Salt Transport Inhibition For Prediction Of Cholestasismentioning

confidence: 99%

High‐Content Analysis/Screening for Predictive Toxicology: Application to Hepatotoxicity and Genotoxicity

Persson

Løye

Jacquet

et al. 2014

Basic Clin Pharma Tox

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High-content imaging/analysis has emerged as a powerful tool for predictive toxicology as it can be used for identifying and mitigating potential safety risks during drug discovery. By careful selection of end-points, some cellular assays can show better predictivity than routine animal toxicity testing for certain adverse events. Here, we present the perhaps most utilized highcontent screening assays for predictive toxicology in the pharmaceutical industry. Multi-parametric imaging of cell health in simple and cost-effective model systems can be used to predict human hepatotoxicity and elucidate mechanisms of toxicity, and imaging of bile salt transport inhibition in sandwich-cultured hepatocytes can be used to predict cholestasis-inducing compounds. Imaging of micronuclei formation in simple cell models can be used to detect genotoxic potential and elucidate anuegenic or clastogenic mode of actions. The hope is that application of these relatively predictive assays during drug discovery will reduce toxicity and safety-related attrition of drug development programmes at later stages. High-Content Imaging/Analysis for Predictive ToxicologyHigh-content imaging and analysis, often referred to as highcontent screening (HCS), has emerged as a powerful tool for assessing molecular, cellular, and tissue-based toxicity, particularly in the field of predictive toxicology. This field of science aims at predicting adverse events in human beings (and pre-clinical species) associated with drug treatment. It is crucial for the pharmaceutical industry to identify and subsequently mitigate potential safety risks early on in the R&D process, and thereby reduce the toxicity and safety-related attrition of drug development programmes at later stages [1]. Here, we review some of the most commonly used HCS assays for predictive toxicology in the pharmaceutical industry, and at Lundbeck in particular. We discuss the background of the readouts, their predictivity and what conclusions can be drawn from them. Particular emphasis will be placed on endpoints that are not well predicted by routine toxicological studies in animals. The Lundbeck strategy for toxicology assessments during the drug discovery process, including assays performed, is described elsewhere [1,2].Since HCS is based on automatized imaging of cells or tissues, typically making use of fluorescent dyes or antibodies, it offers some key advantages over the biochemical assays traditionally used for in vitro toxicology assessments. The main advantages are that the end-points can be assessed at the single-cell level and that multiple end-points can be assessed simultaneously. This enables the user to customize and multiplex end-points and gate for particular cells of interest, which provides an integrated assessment of cellular or molecular toxicity and its mode of action. The multiplexing of different end-points is only limited by the specificity of the employed dyes and antibodies, and their spectral separation. This allows for highly customized assays where the...

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In Vitro Approach to Assess the Potential for Risk of Idiosyncratic Adverse Reactions Caused by Candidate Drugs

Cited by 195 publications

References 65 publications

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model

A testing strategy to predict risk for drug-induced liver injury in humans using high-content screen assays and the ‘rule-of-two’ model

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

High‐Content Analysis/Screening for Predictive Toxicology: Application to Hepatotoxicity and Genotoxicity

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