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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01235

Strategies for early prediction and timely recognition of drug-induced liver injury: the case of CDK4/6 inhibitors

  • 1University of Bologna, Italy
  • 2Department of Medical and Surgical Sciences, University of Bologna, Italy

The idiosyncratic nature of drug-induced liver injury (DILI) represents a current challenge for both 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 CDK4/6 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feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain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, Signal detection analyses, Risk ranking

Received: 26 Jun 2019; Accepted: 27 Sep 2019.

Copyright: © 2019 Raschi and De Ponti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Fabrizio De Ponti, Department of Medical and Surgical Sciences, University of Bologna, Bologna, 40126, Emilia-Romagna, Italy, fabrizio.deponti@unibo.it