Marsot Amélie, Guilhaumou Romain, Riff Camille, Blin Olivier
Service de Pharmacologie Clinique et Pharmacovigilance, AP-HM, Pharmacologie intégrée et interface clinique et industrielle, Institut des Neurosciences Timone, AMU-CNRS 7289, Aix Marseille Université, 13385, Marseille, France.
Clin Pharmacokinet. 2017 Feb;56(2):127-138. doi: 10.1007/s40262-016-0428-x.
Amikacin is an aminoglycoside commonly used in intensive care units for the treatment of patients with life-threatening Gram-negative infections. Although aminoglycosides are extensively used, the accurate determination of their optimal dosage is complicated by marked intra- and interindividual variability in intensive care unit patients. Amikacin pharmacokinetics have been described in numerous studies over the past 25 years.
This review presents a synthesis of the population pharmacokinetic models for amikacin described in critically ill patients. The objective was to determine whether there was a consensus on a structural model and which covariates had been identified.
A literature search was conducted from the PubMed database, from its inception up until December 2015, using the following terms: 'amikacin', 'pharmacokinetic(s)', 'population', 'model(ling)' and 'nonlinear mixed effect'. Articles were excluded if they were not pertinent. The reference lists of all selected articles were also evaluated.
Ten articles were included in this review: pharmacokinetics of amikacin were described by a one-compartment or a two-compartment model. Various covariates were tested, but only two (creatinine clearance and total body weight) were included in almost all of the described models. After inclusion of these covariates, the interindividual variability (range) in clearance and the volume of distribution were 44.4 % (28.2-69.4 %) and 31.3 % (8.1-44.7 %), respectively. The residual variability (range) was around 21.0 % (9.0-31.0 %), using a proportional model, and for a combined model (proportional/additive), the median (range) values were 0.615 mg/L (0.2-1.03 mg/L) and 29.2 % (26.8-31.6 %).
This review highlights the different population pharmacokinetic models for amikacin developed in critically ill patients over the past decades and proposes relevant information for clinicians and researchers. To optimize amikacin dosage, this review points out the relevant covariates according to the target population. In a population of critically ill patients, dose optimization mainly depends on creatinine clearance and total body weight. New pharmacokinetic population studies could be considered, with new covariates of interest to be tested in model building and to further explain variability. Another future perspective could be external evaluation of previously published models.
阿米卡星是一种氨基糖苷类药物，常用于重症监护病房治疗危及生命的革兰氏阴性菌感染患者。尽管氨基糖苷类药物被广泛使用，但在重症监护病房患者中，由于个体内和个体间存在显著差异，准确确定其最佳剂量变得很复杂。在过去25年中，已有大量关于阿米卡星药代动力学的研究报道。
本综述对危重症患者中描述的阿米卡星群体药代动力学模型进行了综合分析。目的是确定在结构模型上是否存在共识，以及已确定了哪些协变量。
使用以下检索词在PubMed数据库中进行文献检索，检索时间从数据库建立至2015年12月：“阿米卡星”、“药代动力学”、“群体”、“模型（构建）”和“非线性混合效应”。排除不相关的文章。还对所有入选文章的参考文献列表进行了评估。
本综述纳入了10篇文章：阿米卡星的药代动力学由一室模型或二室模型描述。测试了各种协变量，但几乎所有描述的模型中仅纳入了两个协变量（肌酐清除率和总体重）。纳入这些协变量后，清除率和分布容积的个体间变异（范围）分别为44.4%（28.2 - 69.4%）和31.3%（8.1 - 44.7%）。使用比例模型时，残余变异（范围）约为21.0%（9.0 - 31.0%），对于组合模型（比例/加和），中位数（范围）值分别为0.615 mg/L（0.2 - 1.03 mg/L）和29.2%（26.8 - 31.6%）。
本综述强调了过去几十年来在危重症患者中建立的不同的阿米卡星群体药代动力学模型，并为临床医生和研究人员提供了相关信息。为优化阿米卡星剂量，本综述根据目标人群指出了相关协变量。在危重症患者群体中，剂量优化主要取决于肌酐清除率和总体重。可以考虑开展新的药代动力学群体研究，在模型构建中测试新的感兴趣的协变量，以进一步解释变异性。另一个未来的方向可能是对先前发表的模型进行外部评估。
