Pressiat Claire, Kudela Agathe, De Roux Quentin, Khoudour Nihel, Alessandri Claire, Haouache Hakim, Vodovar Dominique, Woerther Paul-Louis, Hutin Alice, Ghaleh Bijan, Hulin Anne, Mongardon Nicolas
Laboratoire de Pharmacologie, DMU Biologie-Pathologie, Assistance Publique des Hôpitaux de Paris (APHP), Hôpitaux Universitaires Henri Mondor, 94010 Créteil, France.
Faculté de Santé, Université Paris Est Créteil, 94010 Créteil, France.
Pharmaceutics. 2022 Jan 26;14(2):289. doi: 10.3390/pharmaceutics14020289.
Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) support leads to complex pharmacokinetic alterations, whereas adequate drug dosing is paramount for efficacy and absence of toxicity in critically ill patients. Amikacin is a major antibiotic used in nosocomial sepsis, especially for these patients. We aimed to describe amikacin pharmacokinetics on V-A ECMO support and to determine relevant variables to improve its dosing. All critically ill patients requiring empirical antimicrobial therapy, including amikacin for nosocomial sepsis supported or not by V-A ECMO, were included in a prospective population pharmacokinetic study. This population pharmacokinetic analysis was built with a dedicated software, and Monte Carlo simulations were performed to identify doses achieving therapeutic plasma concentrations. Thirty-nine patients were included (control = 15, V-A ECMO = 24); 215 plasma assays were performed and used for the modeling process. Patients received 29 (24-33) and 32 (30-35) mg/kg of amikacin in control and ECMO groups, respectively. Data were best described by a two-compartment model with first-order elimination. Inter-individual variabilities were observed on clearance, central compartment volume (V) and peripherical compartment volume (V). Three significant covariates explained these variabilities: Kidney Disease Improving Global Outcomes (KDIGO) stage on amikacin clearance, total body weight on V and ECMO support on V. Our simulations showed that the adequate dosage of amikacin was 40 mg/kg in KDIGO stage 0 patients, while 25 mg/kg in KDIGO stage 3 patients was relevant. V-A ECMO support had only a secondary impact on amikacin pharmacokinetics, as compared to acute kidney injury.
静脉-动脉体外膜肺氧合（V-A ECMO）支持会导致复杂的药代动力学改变，而对于危重症患者，适当的药物剂量对于疗效和无毒性至关重要。阿米卡星是医院获得性脓毒症中使用的主要抗生素，尤其是对于这些患者。我们旨在描述V-A ECMO支持下阿米卡星的药代动力学，并确定相关变量以改善其给药剂量。所有需要经验性抗菌治疗的危重症患者，包括接受或未接受V-A ECMO支持治疗医院获得性脓毒症时使用阿米卡星的患者，均纳入一项前瞻性群体药代动力学研究。该群体药代动力学分析使用专用软件构建，并进行蒙特卡洛模拟以确定达到治疗性血浆浓度的剂量。纳入39例患者（对照组 = 15例，V-A ECMO组 = 24例）；进行了215次血浆检测并用于建模过程。对照组和ECMO组患者分别接受29（24 - 33）mg/kg和32（30 - 35）mg/kg的阿米卡星。数据用具有一级消除的二室模型能得到最佳描述。在清除率、中央室容积（V）和外周室容积（V）方面观察到个体间变异性。三个显著的协变量解释了这些变异性：肾脏病改善全球预后（KDIGO）分期对阿米卡星清除率的影响、总体重对V的影响以及V-A ECMO支持对V的影响。我们的模拟表明，KDIGO 0期患者阿米卡星的适当剂量为40 mg/kg，而KDIGO 3期患者25 mg/kg是合适的。与急性肾损伤相比，V-A ECMO支持对阿米卡星药代动力学的影响仅为次要影响。
