American Chemical Society
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Nonclinical Safety Signals in PharmaPendium Improve the Predictability of Human Drug-Induced Liver Injury

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journal contribution
posted on 2022-10-26, 15:36 authored by Payal Rana, Sanaa Khan, Seda Arat, David Potter, Nasir Khan
Drug-induced liver injury (DILI) is a leading cause of candidate attrition during drug development in the pharmaceutical industry. This study evaluated liver toxicity signals for 249 approved drugs (114 of “most-DILI concern” and 135 of “no-DILI concern”) using PharmaPendium and assessed the association between nonclinical and clinical injuries using contingency table analysis. All animal liver findings were combined into eight toxicity categories based on nature and severity. Together, these analyses revealed that cholestasis [odds ratio (OR): 5.02; 95% confidence interval (CI) 1.04–24.03] or liver aminotransferase increases (OR: 1.86; 95% CI 1.09–3.09) in rats and steatosis (OR-1.9; 95% CI 1.03–3.49) or liver aminotransferase increases (OR-2.57; 95% CI 1.4–4.7) in dogs were significant predictors of human liver injury. The predictive value further improved when the liver injury categories were combined into less severe (steatosis, cholestasis, liver aminotransferase increase, hyperbilirubinemia, or jaundice) and more-severe (liver necrosis, acute liver failure, or hepatotoxicity) injuries. In particular, less-severe liver injuries in the following pairs of species predicted human hepatotoxicity {[dog and mouse] (OR: 2.70; 95% CI 1.25–5.84), [dog and rat] (OR-2.61; 95% CI 1.48–4.59), [monkey and mouse] (OR-4.22; 95% CI 1.33–13.32), and [monkey and rat] (OR-2.45; 95% CI 1.15–5.21)} were predictive of human hepatotoxicity. Meanwhile, severe liver injuries in both [dog and rat] (OR-1.9; 95% CI 1.04–3.49) were significant predictors of human liver toxicity. Therefore, we concluded that the occurrence of DILI in humans is highly likely if liver injuries are observed in one rodent and one nonrodent species and that liver aminotransferase increases in dogs and rats can predict DILI in humans. Together, these findings indicate that the liver safety signals observed in animal toxicity studies indicate potential DILI risk in humans and could therefore be used to prioritize small molecules with less potential to cause DILI in humans.