Grensemann Jörn, Pfaffendorf Christoph, Wicha Sebastian G, König Christina, Roedl Kevin, Jarczak Dominik, Iwersen-Bergmann Stefanie, Manthey Carolin, Kluge Stefan, Fuhrmann Valentin
Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246 Hamburg, Germany.
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Bundesstrasse 45, 20146 Hamburg, Germany.
Microorganisms. 2021 Oct 3;9(10):2087. doi: 10.3390/microorganisms9102087.
Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Besides bacteria, molds play a role. Voriconazole (VRC) is recommended but its pharmacokinetics (PK) may be altered by ACLF. Because ACLF patients often suffer from concomitant acute renal failure, we studied the PK of VRC in patients receiving continuous renal replacement therapy (RRT) with ACLF and compared it to PK of VRC in critically ill patients with RRT without concomitant liver failure (NLF). In this prospective cohort study, patients received weight-based VRC. Pre- and post-dialysis membrane, and dialysate samples obtained at different time points were analyzed by high-performance liquid chromatography. An integrated dialysis pharmacometric model was used to model the available PK data. The recommended, 50% lower, and 50% higher doses were analyzed by Monte-Carlo simulation (MCS) for day 1 and at steady-state with a target trough concentration (TC) of 0.5-3mg/L. Fifteen patients were included in this study. Of these, 6 patients suffered from ACLF. A two-compartment model with linear clearance described VRC PK. No difference for central (V1) or peripheral (V2) volumes of distribution or clearance could be demonstrated between the groups. V1 was 80.6L (95% confidence interval: 62.6-104) and V2 106L (65-166) with a body clearance of 4.7L/h (2.87-7.81) and RRT clearance of 1.46L/h (1.29-1.64). MCS showed TC below/within/above target of 10/74/16% on day 1 and 9/39/52% at steady-state for the recommended dose. A 50% lower dose resulted in 26/72/1% (day 1) and 17/64/19% at steady-state and 7/57/37% and 7/27/67% for a 50% higher dose. VRC pharmacokinetics are not significantly influenced by ACLF in critically ill patients who receive RRT. Maintenance dose should be adjusted in both groups. Due to the high interindividual variability, therapeutic drug monitoring seems inevitable.
感染和脓毒症是慢加急性肝衰竭（ACLF）的主要病因。除细菌外，霉菌也起作用。推荐使用伏立康唑（VRC），但其药代动力学（PK）可能因ACLF而改变。由于ACLF患者常伴有急性肾衰竭，我们研究了接受连续性肾脏替代治疗（RRT）的ACLF患者中VRC的PK，并将其与未合并肝衰竭（NLF）的接受RRT的危重症患者中VRC的PK进行比较。在这项前瞻性队列研究中，患者接受基于体重的VRC。通过高效液相色谱法分析透析前、透析后膜以及在不同时间点采集的透析液样本。使用综合透析药代动力学模型对可用的PK数据进行建模。通过蒙特卡洛模拟（MCS）分析第1天和稳态时推荐剂量、降低50%的剂量以及增加50%的剂量，目标谷浓度（TC）为0.5 - 3mg/L。本研究纳入了15名患者。其中，6名患者患有ACLF。用具有线性清除率的二室模型描述VRC的PK。两组之间在中央分布容积（V1）、外周分布容积（V2）或清除率方面未显示出差异。V1为80.6L（95%置信区间：62.6 - 104），V2为106L（65 - 166），机体清除率为4.7L/h（2.87 - 7.81），RRT清除率为1.46L/h（1.29 - 1.64）。MCS显示，对于推荐剂量，第1天TC低于/处于/高于目标值的比例分别为10/74/16%，稳态时为9/39/52%。降低50%的剂量在第1天导致的比例为26/72/1%，稳态时为17/64/19%；增加50%的剂量导致的比例分别为7/57/37%和7/27/67%。在接受RRT的危重症患者中，ACLF对VRC的药代动力学没有显著影响。两组均应调整维持剂量。由于个体间差异较大，治疗药物监测似乎不可避免。
