Hepatic adverse events associated with anaplastic lymphoma kinase tyrosine kinase inhibitors: a disproportionality analysis based on FAERS Database and analysis of drug-gene interaction network

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are vital for treating ALK-positive cancers but have been associated with liver injury, necessitating further safety investigation. This study examines hepatic adverse event (AE) signals related to ALK TKIs using the U.S. FDA Adverse Event Reporting System (FAERS) and explores potential mechanisms of liver injury. AE reports from FAERS (Q3 2011 to Q1 2024) related to liver injury were analyzed using the reporting odds ratio (ROR) and multi-item gamma Poisson shrinker (MGPS) methods. Pathway enrichment and drug-gene network analyses were performed to investigate underlying mechanisms. This study identified 2,132 AE reports from the FAERS database linking hepatic AEs to ALK TKIs therapy. Significant signals were detected by ROR and MGPS methods, with common AEs including aminotransferase abnormalities, hyperbilirubinemia, and increased blood alkaline phosphatase, mainly occurring within the first 30 days of treatment. Gene analysis revealed key nodes in the protein-protein interaction (PPI) network, such as PIK3CA, SRC, and PTK2. Enriched KEGG pathways included the MAPK, PI3K-Akt, and Ras signaling. This pharmacovigilance study identifies significant AE signals linking ALK TKIs to liver injury, highlighting potential mechanisms and providing insights for clinical management and patient outcomes.