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Front Pharmacol. 2019 Oct 24;10:1235. doi: 10.3389/fphar.2019.01235. eCollection 2019.

Strategies for Early Prediction and Timely Recognition of Drug-Induced Liver Injury: The Case of Cyclin-Dependent Kinase 4/6 Inhibitors.

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1
Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy.

Abstract

The idiosyncratic nature of drug-induced liver injury (DILI) represents a current challenge for drug developers, regulators and clinicians. The myriad of agents (including medications, herbals, and dietary supplements) with recognized DILI potential not only strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, but also shows the imperfect predictivity of pre-clinical models and the lack of validated biomarkers beyond traditional, non-specific liver function tests. After briefly reviewing proposed key mechanisms of DILI, we will focus on drug-related risk factors (physiochemical and pharmacokinetic properties) recently proposed as predictors of DILI and use cyclin-dependent kinase 4/6 inhibitors, relatively novel oral anticancer medications approved for breast cancer, as a case study to discuss the feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain insight into drug-related risk factors likely to explain the observed differences.

KEYWORDS:

drug-induced liver injury; hepatotoxicity; predictivity; risk ranking; signal detection

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