CDK4/6 inhibitors in drug-induced liver injury: a pharmacovigilance study of the FAERS database and analysis of the drug-gene interaction network

• Main Authors: Youjun She (Author), Zihan Guo (Author), Qing Zhai (Author), Jiyong Liu (Author), Qiong Du (Author), Zhongwei Zhang (Author)
• Format: Book
• Published: Frontiers Media S.A., 2024-04-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 1663-9812; 10.3389/fphar.2024.1378090
• Keywords: cyclin-dependent kinase 4/6 inhibitors; drug-induced liver injuries; pharmacovigilance; FAERS; disproportionality analyses; protein-protein interaction; Therapeutics. Pharmacology; RM1-950
• Source: Frontiers in Pharmacology, Vol 15 (2024)

Objective:The aim of this study was to investigate the potential risk of drug-induced liver injury (DILI) caused by the CDK4/6 inhibitors (CDK4/6is abemaciclib, ribociclib, and palbociclib by comprehensively analyzing the FDA Adverse Event Reporting System (FAERS) database. Moreover, potential toxicological mechanisms of CDK4/6is-related liver injury were explored via drug-gene network analysis.Methods:In this retrospective observational study, we collected reports of DILI associated with CDK4/6i use from the FAERS dated January 2014 to March 2023. We conducted disproportionality analyses using the reporting odds ratio (ROR) with a 95% confidence interval (CI). Pathway enrichment analysis and drug-gene network analyses were subsequently performed to determine the potential mechanisms underlying CDK4/6i-induced liver injury.Results:We found positive signals for DILI with ribociclib (ROR = 2.60) and abemaciclib (ROR = 2.37). DILIs associated with liver-related investigations, signs, and symptoms were confirmed in all three reports of CDK4/6is. Moreover, ascites was identified as an unlisted hepatic adverse effect of palbociclib. We isolated 189 interactive target genes linking CDK4/6 inhibitors to hepatic injury. Several key genes, such as STAT3, HSP90AA1, and EP300, were revealed via protein-protein analysis, emphasizing their central roles within the network. KEGG pathway enrichment of these genes highlighted multiple pathways.Conclusion:Our study revealed variations in hepatobiliary toxicity among the different CDK4/6 inhibitors, with ribociclib showing the highest risk of liver injury, followed by abemaciclib, while palbociclib appeared relatively safe. Our findings emphasize the need for cautious use of CDK4/6 inhibitors, and regular liver function monitoring is recommended for long-term CDK4/6 inhibitor use.