Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Department of Critical Care Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Int J Infect Dis. 2020 Apr;93:345-352. doi: 10.1016/j.ijid.2020.02.041. Epub 2020 Feb 25.
To characterize the pharmacokinetics (PK) of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction.
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.
There were good correlations between the area under the curve (AUC) of PK curve 2 and the corresponding trough concentration (C) and peak concentration (C) (r = 0.951 and 0.963, respectively; both p < 0.001). The median half-life (t) 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) of PK curve 1 was positively correlated with actual body weight (r = 0.450, p = 0.004). The median first C of 17 patients determined on day 5 was 5.27 (2.61) μg/ml, and 29.4% of C exceeded the upper limit of the therapeutic window (2-6 μg/ml).
The CL of VRC decreased with increasing severity of liver dysfunction according to the Child-Pugh classification, along with an increased t, which resulted in high plasma exposure of VRC. Adjusted dosing regimens of intravenous VRC should be established based on Child-Pugh classes for these ICU patients, and plasma concentrations should be monitored closely to avoid serious adverse events.
描述肝功能障碍的重症监护病房（ICU）患者中静脉用伏立康唑（VRC）的药代动力学（PK）特征。
前瞻性纳入肝功能障碍的 ICU 患者。采用Child-Pugh 评分对肝功能障碍的严重程度进行分类。初始静脉 VRC 给药方案包括前 24 小时每 12 小时给予负荷剂量 300mg，然后每 12 小时给予 200mg。17 例患者在首次剂量的一个给药间隔内绘制第一次 PK 曲线（PK 曲线 1）；12 例患者在至少 7 次剂量后一个给药间隔内绘制第二次 PK 曲线（PK 曲线 2）。通过非房室分析估算 PK 参数。
PK 曲线 2 的 AUC 与相应的谷浓度（C）和峰浓度（C）之间存在良好的相关性（r = 0.951 和 0.963，均 p < 0.001）。PK 曲线 2 中 Child-Pugh 分级 A（n = 3）、B（n = 5）和 C（n = 4）患者的中位半衰期（t）和清除率（CL）分别为 24.4 小时和 3.31 l/h、29.1 小时和 2.54 l/h、60.7 小时和 2.04 l/h。在不同的 Child-Pugh 分级中，PK 曲线 2 的 CL（中位数）均低于 PK 曲线 1。PK 曲线 1 的表观稳态分布容积（V）与实际体重呈正相关（r = 0.450，p = 0.004）。17 例患者第 5 天首次 C 的中位数为 5.27（2.61）μg/ml，29.4%的 C 超过治疗窗上限（2-6μg/ml）。
根据 Child-Pugh 分类，VRC 的 CL 随着肝功能障碍严重程度的增加而降低，同时 t 增加，导致 VRC 的血浆暴露量增加。对于这些 ICU 患者，应根据 Child-Pugh 分级制定静脉用 VRC 的调整给药方案，并密切监测血浆浓度，以避免严重的不良反应。
