基于FAERS数据库的儿童唑类抗真菌药物相关肝损伤研究

Analysis of Azole Antifungals related Liver Injury in Children Based on FAERS

关键词:  唑类抗真菌药物  肝损伤  儿童  FDA不良事件报告系统  不良事件

Key words:  azole antifungals  liver injury  children  FDA adverse event reporting system  adverse events

摘要:

目的 基于美国食品药品监督管理局不良事件报告系统数据库（FAERS），研究分析儿童唑类抗真菌药物的肝损伤不良事件，为临床安全使用提供参考。方法 提取氟康唑、伊曲康唑、伏立康唑、泊沙康唑、艾沙康唑的不良事件报告，并采用比例失衡法和贝叶斯法进行不良事件信号挖掘，对儿童肝损伤相关报告进行分析。结果 共提取5种唑类抗真菌药物的儿童肝损伤报告360份，伏立康唑和氟康唑报告数最多，分别为185例和87例。年龄主要分布于青少年（43.06%），伊曲康唑幼儿比例最高（43.33%），男女性别比例1:1.24。发生肝损伤的时间主要集中在30天内，最常报告的合用药物包括两性霉素B、甲氨蝶呤、环孢素等。所有唑类药物均检出肝损伤的阳性信号，信号值较高的是伏立康唑的脂肪性肝炎（6例，ROR 172.80，PRR 171.85，EBGM05 47.65）和艾沙康唑的急性肝衰竭（8例，ROR 77.49，PRR 65.01，EBGM05 30.21），其中脂肪性肝炎为新的信号。结论 唑类抗真菌药物均有致儿童肝损伤风险，发生时间主要集中在30天内，合用肝毒性药物和相互作用药物可能增加肝损伤风险，具体临床表型和风险因素仍需临床研究验证。

Abstract:

OBJECTIVE To study and analyze liver injury induced by azole antifungals in children based on the FDA Adverse Event Reporting System, aiming to provide more evidences for clinical drug safety. METHODS Adverse event reports of fluconazole, itraconazole, voriconazole, posaconazole, and isavuconazole were extracted. Disproportionality analysis and Bayesian methods were used to detect signals, with further analysis conducted on liver injury reports associated with azole antifungals in children. RESULTS A total of 360 liver injury reports related to azole antifungals in children were extracted. Voriconazole and fluconazole were reported most frequently, with 185 and 87 cases respectively. Adolescents comprised the majority of the reports (43.06%), while toddlers were most frequently reported for itraconazole (43.33%). The gender ratio was 1:1.24. The onset of liver injury primarily occurred within 15 days. The most commonly reported concomitant medications were amphotericin B, methotrexate, and cyclosporine. Positive signals for liver injury were detected in all azole antifungals. The highest signal values was steatohepatitis with voriconazole (6 cases, ROR 172.80, PRR 171.85, EBGM05 47.65) and acute liver failure with isavuconazole (8 cases, ROR 77.49, PRR 65.01, EBGM05 30.21). Steatohepatitis was a new signal. CONCLUSION All azole antifungals have the risk of causing liver injury in children, primarily occurring within 30 days. Co-administration of hepatotoxic and interacting drugs may increase the risk of liver injury, specific phenotypes and risk factors still need to be verified by clinical studies.