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

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feasibility of early detection of DILI signals during drug development: published data from pivotal clinical trials, unpublished post-marketing reports of liver adverse events, and pharmacokinetic properties will be used to provide a comparative evaluation of their liver safety and gain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.

Cyclin-dependent kinase 4/6 inhibitors and interstitial lung disease in the FDA adverse event reporting system: a pharmacovigilance assessment

“…In the past few years, the therapeutic scenario of hormone receptor-positive, epidermal growth factor receptor 2-negative, advanced/metastatic breast cancer has been profoundly changed by the clinical availability of CDK4/6 inhibitors. These agents differ in terms of tolerability (gastrointestinal, liver, and bone marrow toxicities), with relevant impact on safe prescribing by oncologists [ 1 – 5 ].…”

“…The most common side effect for palbociclib and ribociclib is neutropenia, whereas gastrointestinal toxicity is associated especially with abemaciclib (showing less selectivity for CDK4, which plays a critical role in hematopoietic stem cell differentiation) [ 4 ]. Among rare adverse events, higher frequency of QT prolongation emerged for ribociclib, whereas transaminases increase was recorded with ribociclib and abemaciclib resulting in regulatory warnings [ 5 ].…”

Liver Injury with Ulipristal Acetate: Exploring the Underlying Pharmacological Basis

“…Therefore, to explore the relationship between the use of UPA and the occurrence of DILI, we implemented a "twostep" approach based on (1) analysis of spontaneous reports submitted to the US FDA Adverse Event Reporting System (FAERS) database, including disproportionality analysis for hepatic reactions classified as designated medical events (DMEs), namely rare serious adverse events (AEs) with a recognized drug-attributable risk [9]; and (2) review of physiochemical and pharmacokinetic features known to be potentially involved in DILI. metabolism, and inhibition of hepatic transporters can confer a risk for DILI, which may increase susceptibility to hepatotoxicity because of host-related factors such as female sex and age [14,15].…”

Ulipristal acetate and liver-injuries: while Esmya is revoked, EllaOne is allowed in repeated self-administrations possibly exceeding UPA toxic-dosing with Esmya

“…The burden of DILI is likely underestimated: clinical trials are usually underpowered to identify rare idiosyncratic events and most data come from post-marketing retrospective studies. DILI occurs only in a small fraction of exposed-subjects [9] : with UPA the percentage was 1/10.000: 8 out of 80.0000 Esmyapatients, but ellaOne is taken by millions of women every year and repeated-self-administration cannot be quantified. EllaOne is not subject to medical prescription, so no data are available for post-marketing evaluation.…”

“…The most challenging form of DILI is the so-called idiosyncratic one: it is unpredictable, usually unrelated to the dose and is characterized by a variable onset-time. DILI is an important public health issue: not only it 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 [9] .…”