Unveiling the hidden risk of caspofungin: Insights from three adverse event reporting systems and network pharmacology integration

Zhengfu Li¹Zhiwei Cui²De Xie³Fan Zou^1*Chengyu Zhu^1*

• ¹Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
• ²Department of Obstetrics and Gynecology, First Affiliated Hospital of Xi’an Jiaotong University, Xi'an, Shaanxi, China
• ³Department of Internal Medicine, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian Province, China

Background: Caspofungin, the first FDA-approved echinocandin antifungal agent, plays a vital role in managing invasive fungal infections (IFIs). Despite its established efficacy, large-scale real-world safety evaluations remain limited. This study provides a comprehensive pharmacovigilance analysis of caspofungin's safety profile.: Adverse drug events (ADEs) associated with caspofungin were extracted from the FDA Adverse Event Reporting System (FAERS), the Japanese Adverse Drug Event Reporting Database (JADER), and the Canadian Vigilance Adverse Reaction Database (CVARD) databases. Signal detection utilized four methods: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multiple gamma-Poisson shrinkage (MGPS).Time-to-onset (TTO) analysis was conducted using FAERS data, and network pharmacology approaches were employed to investigate potential molecular mechanisms, particularly in caspofungin-inducedrelated liver injury.Results: A total of 2,270, 161, and 128 ADE reports were retrieved from FAERS, JADER, and CVARD, respectively. "Hepatobiliary disorders" and "infections and infestations" are overlapping positive signals from three databases at the system organ class level. ADEs such as hypokalemia, sepsis, and drug ineffectiveness were consistent with the drug label. Unexpected signals included prolonged QT interval, cardiac arrest, septic shock, and cholestasis. Cross-database overlap included "drug ineffective" and "toxic skin eruption" between FAERS and JADER, and "renal failure","photodermatitisphotodermatotis" between FAERS and CVARD. TTO analysis revealed that 89.95% of ADEs occurred within the first month, with a median onset time of 6 days. Network pharmacology identified PI3K/Akt and HIF-1 pathways as mechanisms underlying caspofungin-induced liver injury.This study highlights both expected and unexpected ADEs of caspofungin, emphasizing the importance of clinical vigilance and molecular research to enhance patient safety and therapeutic outcomes.