Amann Lisa F, Alraish Rawan, Broeker Astrid, Kaffarnik Magnus, Wicha Sebastian G
Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, 20146 Hamburg, Germany.
Department of Surgery, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
Antibiotics (Basel). 2022 Apr 3;11(4):479. doi: 10.3390/antibiotics11040479.
This study investigated tigecycline exposure in critically ill patients from a population pharmacokinetic perspective to support rational dosing in intensive care unit (ICU) patients with acute and chronic liver impairment. A clinical dataset of 39 patients served as the basis for the development of a population pharmacokinetic model. The typical tigecycline clearance was strongly reduced (8.6 L/h) as compared to other populations. Different models were developed based on liver and kidney function-related covariates. Monte Carlo simulations were used to guide dose adjustments with the most predictive covariates: Child-Pugh score, total bilirubin, and MELD score. The best performing covariate, guiding a dose reduction to 25 mg q12h, was Child-Pugh score C, whereas patients with Child-Pugh score A/B received the standard dose of 50 mg q12h. Of note, the obtained 24 h steady-state area under the concentration vs. time curve (AUC) range using this dosing strategy was predicted to be equivalent to high-dose tigecycline exposure (100 mg q12h) in non-ICU patients. In addition, 26/39 study participants died, and therapy failure was most correlated with chronic liver disease and renal failure, but no correlation between drug exposure and survival was observed. However, tigecycline in special patient populations needs further investigations to enhance clinical outcome.
本研究从群体药代动力学角度调查了重症患者的替加环素暴露情况，以支持对急性和慢性肝功能损害的重症监护病房（ICU）患者进行合理给药。39例患者的临床数据集作为建立群体药代动力学模型的基础。与其他人群相比，替加环素的典型清除率大幅降低（8.6 L/h）。基于与肝肾功能相关的协变量开发了不同的模型。采用蒙特卡洛模拟法，以预测性最强的协变量（Child-Pugh评分、总胆红素和终末期肝病模型（MELD）评分）指导剂量调整。表现最佳的协变量是Child-Pugh C级评分，它指导剂量减至25 mg q12h，而Child-Pugh A/B级评分的患者接受50 mg q12h的标准剂量。值得注意的是，使用该给药策略获得的24小时稳态血药浓度-时间曲线下面积（AUC）范围预计与非ICU患者高剂量替加环素暴露（100 mg q12h）相当。此外，39名研究参与者中有26人死亡，治疗失败与慢性肝病和肾衰竭的相关性最大，但未观察到药物暴露与生存之间的相关性。然而，特殊患者群体中的替加环素需要进一步研究以改善临床结局。
