Host: The Japanese Society of Toxicology
In the patients treated with BACE (beta-site amyloid precursor protein cleaving enzyme) inhibitor Atabecestat, elevation of live enzymes was observed after dosing. In immunohistochemistry using liver biopsy sample from one patient induced liver injury, an adaptive, T-cell mediated response was noted. Furthermore, in using PBMC treated with Atabecestat and its metabolites, IFN-gamma and IL-13 increased. Taken together, one of the mechanisms of Atabecestat induced hepatotoxicity is seems to be immune mediated. In rats 4-wk toxicology study, necrosis of hepatocyte and cellular infiltration and/or hypertrophy of hepatocyte with high values of aspartate aminotransferase (AST), alanine aminotransferase (ALT) were occurred at higher doses. On the other hand, in dog 4-wk study, only slight elevation of AST and ALT without histopathological changes was observed at a highest dose. We recognized Atabecestat has potential of hepatotoxicity induced, highly covalent-binding and active metabolite. However, because there were species different and large safety margin, we decided to develop. The exposure of clinical dose that showed hepatotoxicity was still enough safety margin in non-clinical toxicology studies, but in fact, hepatotoxicity was occurred in clinical study. Because hepatotoxicity induced by Atabecestat may be considered immune mediated, so, it may be difficult to estimate hepatotoxicity in clinical study. However, as a toxicologist, we really carefully use safety margin and should try to investigate and reveal toxicology mechanism in non-clinical study under the development.
