Recent advances in understanding the hepatotoxicity associated with protein kinase inhibitors

ABSTRACT

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.

KEYWORDS:

• Boxed warnings
• drug induced liver injury
• hepatocytes
• hepatotoxicity
• mitochondria
• protein kinase inhibitors
• regorafenib

Article highlights

• Protein kinase inhibitors accounted for about 10% of all FDA-approved new drugs in the past two decades

• Hepatotoxicity appeared to be a major safety issue in premarketing evaluation of protein kinase inhibitors

• Post-marketing surveillance is needed to ascertain the hepatotoxicity potential of many protein kinase inhibitors

• The mechanisms and predictive models for hepatotoxicity associated with protein kinase inhibitor have not been established

• The possible mechanisms of hepatotoxicity for 14 approved protein kinase inhibitors were summarized in this review

This box summarizes key points contained in the article.

Acknowledgments

The authors thank Dr. Laura K. Schnackenberg for critically reading the manuscript and providing many constructive suggestions.

Declaration of interest

All authors are employees of the U.S. Food and Drug Administration. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Disclaimer

The information in these materials is not a formal dissemination of information by the US Food and Drug Administration and does not represent agency position or policy.

Additional information

Funding

This work was supported by the U.S. Food and Drug Administration (FDA) [grant number E0767201].