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feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain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.
Highlights
Prediction and Detection of Drug-Induced Liver Injury where randomized clinical trials are hardly feasible for ethical and methodological issues, the vast majority of recommendations stem from evidence graded to be of low quality, with the exception of immune checkpoint inhibitors, inducing hepatotoxicity in a substantial proportion of individuals, especially in combination regimens
This review, not intended as comprehensive, aims at: 1) providing brief key insights into proposed mechanisms of idiosyncratic drug-induced liver injury (DILI), focusing on drug-related risk factors; b) using cyclin-dependent kinase (CDK)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
Higher frequency of QT prolongation emerged for ribociclib, whereas increased liver enzymes was recorded with ribociclib and abemaciclib resulting in regulatory warnings, with specific recommendations for monitoring liver function test, eventual dose interruption or drug discontinuation (Thill and Schmidt, 2018)
Summary
Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy. The myriad of agents (including medications, herbals, and dietary supplements) with recognized DILI potential strengthens the importance of the post-marketing phase, when urgent withdrawal sometimes occurs for rare unanticipated liver toxicity, and 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
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