Real-world safety profile and mechanistic insights into regorafenib-induced liver failure: a pharmacovigilance study integrated with network toxicology
Related Experiment Video
Updated: Jan 29, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Haonan Sun1, Heng Gu1, Pengkai Xu1
1Department of Hepatobiliary Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China.
Background:
Regorafenib is a multikinase inhibitor widely used in oncology, but it is associated with significant adverse events (AEs), particularly hepatotoxicity. Understanding the real-world safety profile and the molecular mechanisms underlying regorafenib-induced liver failure is critical for clinical risk management.
Methods:
AE reports with regorafenib as the primary suspect drug were extracted from the FDA Adverse Event Reporting System (FAERS) from Q3 2012 to Q1 2025. Disproportionality analyses were conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). Clinical prioritization was assessed via a semi-quantitative framework. Time-to-onset was analyzed using Weibull distribution. Additionally, network toxicology and molecular docking were employed to explore potential mechanisms and binding affinities between regorafenib and liver failure targets.
Results:
A total of 9,442 AE reports were analyzed. Hepatobiliary disorders exhibited the strongest signal strength (ROR = 2.66, 95% CI: 2.50-2.83), with hepatic failure and fulminant hepatitis identified as high-priority AEs. The majority of AEs occurred within 30 days of treatment initiation. Subgroup analysis indicated that elderly patients (≥65 years) and males had higher risks of liver failure, whereas higher body weight appeared protective. Network analysis identified 63 overlapping targets, with MAPK and PI3K-Akt signaling pathways significantly enriched.
Conclusion:
This pharmacovigilance analysis identifies regorafenib-associated hepatotoxicity as a significant safety signal, with higher risks observed in elderly and male patients. Computational predictions suggest the involvement of MAPK and PI3K-Akt pathways, offering a theoretical basis for further mechanistic investigation and supporting the need for vigilant clinical monitoring.
Insights
Regorafenib use is linked to significant liver injury, especially in elderly males. This study highlights the need for careful monitoring due to identified safety signals and potential pathway involvement.
Area of Science:
- Pharmacovigilance
- Oncology
- Toxicology
Background:
- Regorafenib, a multikinase inhibitor, is crucial in cancer treatment but poses risks of adverse events (AEs), notably hepatotoxicity.
- Understanding regorafenib's real-world safety and the mechanisms behind its liver toxicity is vital for managing patient risk.
Purpose of the Study:
- To analyze real-world adverse event reports for regorafenib to identify safety signals, particularly hepatotoxicity.
- To investigate potential molecular mechanisms and risk factors associated with regorafenib-induced liver failure.
Main Methods:
- Extracted 9,442 AE reports from FDA FAERS (Q3 2012-Q1 2025) suspecting regorafenib.
- Employed disproportionality analyses (ROR, PRR, MGPS, BCPNN) and clinical prioritization.
- Utilized network toxicology and molecular docking to explore mechanisms and binding affinities.
Main Results:
- Hepatobiliary disorders showed the strongest safety signal (ROR=2.66), with hepatic failure and fulminant hepatitis as high-priority AEs.
- Most AEs occurred within 30 days; elderly patients (≥65 years) and males faced higher liver failure risks.
- Network analysis implicated MAPK and PI3K-Akt signaling pathways, with 63 overlapping targets identified.
Conclusions:
- Regorafenib-associated hepatotoxicity is a significant safety concern, particularly in elderly males.
- Computational analysis suggests MAPK and PI3K-Akt pathways are involved, providing a basis for further research.
- Vigilant clinical monitoring is essential for patients receiving regorafenib.
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