Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database

Zhi-Xuan Zhou; Xue-Dong Yin; Yu Zhang; Qi-Hui Shao; Xin-Yu Mao; Wen-Juan Hu; Yun-Lin Shen; Bin Zhao; Zhi-Ling Li

doi:10.3389/fphar.2022.891336

Antifungal Drugs and Drug-Induced Liver Injury: A Real-World Study Leveraging the FDA Adverse Event Reporting System Database

Front Pharmacol. 2022 Apr 28:13:891336. doi: 10.3389/fphar.2022.891336. eCollection 2022.

Authors

Zhi-Xuan Zhou^{1

2}, Xue-Dong Yin^{1

2}, Yu Zhang^{1

3}, Qi-Hui Shao^{1

2}, Xin-Yu Mao^{1

2}, Wen-Juan Hu¹, Yun-Lin Shen⁴, Bin Zhao⁵, Zhi-Ling Li¹

Affiliations

¹ Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
² Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Pharmacy, Nanyang Central Hospital, Affiliated Hospital of Zhengzhou University, Nanyang, China.
⁴ Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
⁵ Pharmacy Department, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.

Abstract

Aims: We aimed to estimate the risk of drug-induced liver injury (DILI) from various antifungal treatments with azoles and echinocandins causing in real-world practice. Methods: We performed disproportionality and Bayesian analyses based on data from the first quarter in 2004 to the third quarter in 2021 in the Food and Drug Administration Adverse Event Reporting System to characterize the signal differences of antifungal drugs-related DILI. We also compared the onset time and mortality differences of different antifungal agents. Results: A total of 2943 antifungal drugs-related DILI were identified. Affected patients tended to be aged >45 years (51.38%), with more males than females (49.03% vs. 38.09%). Antifungal drug-induced liver injury is most commonly reported with voriconazole (32.45%), fluconazole (19.37%), and itraconazole (14.51%). Almost all antifungal drugs were shown to be associated with DILI under disproportionality and Bayesian analyses. The intraclass analysis of correlation between different antifungal agents and DILI showed the following ranking: caspofungin (ROR = 6.12; 95%CI: 5.36-6.98) > anidulafungin (5.15; 3.69-7.18) > itraconazole (5.06; 4.58-5.60) > voriconazole (4.58; 4.29-4.90) > micafungin (4.53; 3.89-5.27) > posaconazole (3.99; 3.47-4.59) > fluconazole (3.19; 2.93-3.47) > ketoconazole (2.28; 1.96-2.64). The onset time of DILI was significantly different among different antifungal drugs (p < 0.0001), and anidulafungin result in the highest mortality rate (50.00%), while ketoconazole has the lowest mortality rate (9.60%). Conclusion: Based on the Food and Drug Administration Adverse Event Reporting System database, antifungal drugs are significantly associated with DILI, and itraconazole and voriconazole had the greatest risk of liver injury. Due to indication bias, more clinical studies are needed to confirm the safety of echinocandins.

Keywords: DILI; adverse event reporting system; antifungal drugs; epidemiology; pharmacovigilance.