Pharmacokinetics of intravenous voriconazole in patients with liver dysfunction: A prospective study in the intensive care unit

作者：Xiaobin Lin, Huang Fa, Tong Li, Yanzhe Xia, Jingjing Wu, Jia Li, Xiaoguang Hu, Tao Liang, Xiaoman Liu, Guo-ping Zhong, Chang-jie Cai, Xiao Chen · 发表于：International Journal of Infectious Diseases · 年份：2020 · DOI：10.1016/j.ijid.2020.02.041 · 被引用次数：29 · 研究领域：Antifungal resistance and susceptibility、Neutropenia and Cancer Infections、Neutrophil, Myeloperoxidase and Oxidative Mechanisms

Objectives To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction. Methods Patients with liver dysfunction in the intensive care unit (ICU) were included prospectively. The Child–Pugh score was used to categorize the degree of liver dysfunction. The initial intravenous VRC dosing regimen comprised a loading dose of 300 mg every 12 h for the first 24 h, followed by 200 mg every 12 h. The first PK curves (PK curve 1) were drawn within one dosing interval of the first dose for 17 patients; the second PK curves (PK curve 2) were drawn within one dosing interval after a minimum of seven doses for 12 patients. PK parameters were estimated by non-compartmental analysis. Results There were good correlations between the area under the curve (AUC 0–12 ) of PK curve 2 and the corresponding trough concentration ( C 0 ) and peak concentration ( C max ) ( r 2 = 0.951 and 0.963, respectively; both p < 0.001). The median half-life ( t 1/2 ) and clearance (CL) of patients in Child–Pugh class A ( n = 3), B ( n = 5), and C ( n = 4) of PK curve 2 were 24.4 h and 3.31 l/h, 29.1 h and 2.54 l/h, and 60.7 h and 2.04 l/h, respectively. In the different Child–Pugh classes, the CL (median) of PK curve 2 were all lower than those of PK curve 1. The apparent steady-state volume of distribution ( V ss ) of PK curve 1 was positively correlated with actual body weight ( r 2 = 0.450, p = 0.004). The median first C 0 of 17 patients determi...