In 1993, 7 of 15 clinical trial participants treated for hepatitis B with a nucleoside analogue called fialuridine developed acute liver failure, leading to 5 deaths and 2 liver transplants. A retrospective analysis of all preclinical fialuridine studies conducted in mice, rats, dogs, and monkeys found no indication of liver toxicity. Now, a new mouse model with “humanized” livers appears to be able to detect such a danger (Xu D et al. PLoS Med. 2014;11:e1001628).
In the mouse model, more than 90% of the cells of the animal’s liver are human liver cells. When researchers from the Stanford University School of Medicine and their colleagues administered fialuridine to mice with humanized livers, the drug clearly caused liver failure, with clinical symptoms, laboratory abnormalities, and anatomical changes to the liver mirroring those observed in human participants in the fialuridine trial.