Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors

Introduction: As of October 2019, the U.S. Food and Drug Administration (FDA) has approved 53 small molecule kinase inhibitors (KI), which account for about 10% of all FDA-approved new molecular entities and new biologics in the past two decades. Yet, hepatotoxicity is a major safety concern with KIs, as reflected by 35 KIs having warnings for liver injury in drug labeling, among which seven are boxed warnings. In spite of that, KI hepatotoxicity remains a relatively under-investigated area.Areas covered: This review aims to summarize recent advances in the study of KI hepatotoxicity including the definition, mechanisms, and predictors of KI hepatotoxicity. Data sources include PubMed, LiverTox and the FDA official website.Expert opinion: The hepatotoxicity potential of many KIs has not yet been fully established and therefore the predictive power of in vitro or in silico models cannot be accurately assessed at present. Two KIs accumulated in the liver at concentrations of 10- to 25-fold blood levels, highlighting the importance of normalizing the test concentrations in in vitro models to tissue but blood levels. Pluripotent stem cell-derived hepatocyte-like cells and genotyping of leucocyte antigen (HLA) showed early promise in identifying the individuals who were highly susceptible to KI hepatotoxicity and warrant further investigation.