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.

in Expert opinion on drug safety by Yan Huo, Minghua Ma, Weiwei Tian, Fang Wang, Xiaolan Liao

TLDR

  • This study identified significant adverse event signals linking ALK TKIs to liver injury and provided insights into potential mechanisms and underlying pathways.

Abstract

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.

Overview

  • The study investigates the hepatic adverse event (AE) signals related to Anaplastic Lymphoma Kinase (ALK) tyrosine kinase inhibitors (TKIs) using the FDA Adverse Event Reporting System (FAERS)
  • The study analyzed AE reports from FAERS (Q3 2011 to Q1 2024) related to liver injury using the reporting odds ratio (ROR) and multi-item gamma Poisson shrinker (MGPS) methods to identify significant signals and underlying mechanisms
  • The primary objective of the study is to identify potential mechanisms of liver injury and provide insights for clinical management and patient outcomes

Comparative Analysis & Findings

  • The study identified 2,132 AE reports from the FAERS database linking hepatic AEs to ALK TKIs therapy, with significant signals detected by ROR and MGPS methods
  • Common AEs included 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, and enriched KEGG pathways including the MAPK, PI3K-Akt, and Ras signaling

Implications and Future Directions

  • The study highlights the importance of pharmacovigilance in monitoring the safety of ALK TKIs and identifying potential mechanisms of liver injury
  • Future studies can build on the findings of this study by incorporating molecular biomarkers and investigating novel therapeutic strategies to mitigate liver toxicity
  • The study's findings can inform clinical management and patient outcomes by providing insights into the potential mechanisms of liver injury and enabling early detection and treatment of adverse events
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