Journal
TOXICOLOGICAL SCIENCES
Volume 147, Issue 2, Pages 500-514Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfv152
Keywords
drug-induced liver injury; plasma exposure; Liver Toxicity Knowledge Base; safety margin
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Funding
- Drug Safety Research and Development Science & Technology grant
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Severe drug-induced liver injury (DILI) remains a major safety issue due to its frequency of occurrence, idiosyncratic nature, poor prognosis, and diverse underlying mechanisms. Numerous experimental approaches have been published to improve human DILI prediction with modest success. A retrospective analysis of 125 drugs (70 = most-DILI, 55 = no-DILI) from the Food and Drug Administration Liver Toxicity Knowledge Base was used to investigate DILI prediction based on consideration of human exposure alone or in combination with mechanistic assays of hepatotoxic liabilities (cytotoxicity, bile salt export pump inhibition, or mitochondrial inhibition/uncoupling). Using this dataset, human plasma C-max,C- total >= 1.1 mu M alone distinguished most-DILI from no-DILI compounds with high sensitivity/specificity (80/73%). Accounting for human exposure improved the sensitivity/specificity for each assay and helped to derive predictive safety margins. Compounds with plasma C-max,C- total >= 1.1 mu M and triple liabilities had significantly higher odds ratio for DILI than those with single/dual liabilities. Using this approach, a subset of recent pharmaceuticals with evidence of liver injury during clinical development was recognized as potential hepatotoxicants. In summary, plasma C-max,C- total >= 1.1 mu M along with multiple mechanistic liabilities is a major driver for predictions of human DILI potential. In applying this approach during drug development the challenge will be generating accurate estimates of plasma C-max,C- total at efficacious doses in advance of generating true exposure data from clinical studies. In the meantime, drug candidates with multiple hepatotoxic liabilities should be deprioritized, since they have the highest likelihood of causing DILI in case their efficacious plasma C-max,C- total in humans is higher than anticipated.
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