کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2602447 | 1562715 | 2015 | 9 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Minimizing DILI risk in drug discovery — A screening tool for drug candidates Minimizing DILI risk in drug discovery — A screening tool for drug candidates](/preview/png/2602447.png)
• The risk of idiosyncratic DILI of drug candidates can be reduced by combining assays covering different mechanisms.
• The strategy is applicable to early stages when risk mitigation is still possible.
• Dose- and exposure-based calibration of the assays leads to markedly improved accuracy.
Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process.Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates – according to the FDA categorization – were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.
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Journal: Toxicology in Vitro - Volume 30, Issue 1, Part B, 25 December 2015, Pages 429–437