The Role of Plasma Trough Concentration of Voriconazole and Voriconazole N-Oxide in Its Hepatotoxicity in Adult Patients

Lin Cheng, Xi You, Xiaowen Wang, Mingjie Yu, Changsheng Jia Department of Pharmacy, the First Affiliated Hospital of Army Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Lin Cheng; Mingjie Yu, Email cheng7zhu@163.com; ymjxnyy@163.comObjective: Hepatotoxicity is an important cause of early withdrawal of voriconazole (VCZ). The role of the plasma trough concentration of VCZ (C0) in hepatotoxicity is confusion. VCZ N-oxide is the primary metabolite of VCZ in plasma. We investigated the role of VCZ C0 and plasma trough concentration of VCZ N-oxide (CN) in hepatotoxicity in adult patients.Materials and Methods: This was a prospective study. VCZ C0 and CN were measured using liquid chromatography-tandem mass spectrometry.Results: In total, 601 VCZ C0 and CN from 376 adult patients were included. The percentage of grade 1 or higher adverse events for ALP, ALT, AST, γ-GT, and TBIL were 35.4%, 21.0%, 30.1%, 56.2%, and 22.2%, respectively. Compared with younger adult patients, elderly patients (≥ 65 years) had a higher rate of grade 1 or higher adverse events of ALP. In the multivariate analysis, VCZ C0 was a risk factor for grade 1 or higher adverse events of AST in elderly patients and TBIL in younger adult patients, and VCZ CN was a risk factor for grade 1 or higher adverse events of ALT, AST, and TBIL. Results of the receiver operating characteristic curve analysis indicated that when the VCZ C0 was higher than 4.0 μg/mL, or the VCZ CN was lower than 1.7 μg/mL, the incidence of grade 1 or higher adverse events of AST and TBIL increased.Conclusion: VCZ C0 and CN were associated with liver function-related adverse events. Measurement of VCZ CN should be considered for VCZ therapeutic drug monitoring.Keywords: voriconazole, voriconazole N-oxide, hepatotoxicity, therapeutic drug monitoring