創薬研究段階における in vitro 肝毒性評価系の運用と事例紹介

抄録

　Drug-Induced Liver Injury (DILI) is a main leading cause of attrition in drug development or post-marketing withdrawal. Though the importance of risk assessment of DILI is widely recognized, quantitative DILI assessment is difficult because multiple different mechanism and patient variability complicatedly contribute to human DILI. Extrapolating the animal data to human is also difficult. Consequently, our challenges are that the human risk of DILI could be detected based on the DILI mechanisms in the exploratory stage of drug development and predicted quantitatively by integrating various factors.

　In the exploratory stages, we conduct in vitro assays (e.g. reactive metabolites, mitochondrial toxicity, and bile salt transporter inhibition) and estimate physicochemical properties to profile DILI risk. Remaining issues of quantitative human DILI risk assessment are integrating multiple in vitro assay results and human variability, although in vitro studies can profile DILI mechanism. To solve these issues, we have investigated the usefulness of DILIsym^® developed by DILIsym Services, Inc. in collaboration with FDA, which is cutting-edge modeling and simulation technology.

　This session will highlight in vitro/in silico risk profiling of human DILI in exploratory stages of drug development and retrospective evaluation of the drugs with the elevation of blood liver enzymes in the clinical studies.