Background and Objective

Previous pharmacokinetic (PK) studies of ciprofloxacin in intensive care (ICU) patients have shown large differences in estimated PK parameters, suggesting that further investigation is needed for this population. Hence, we performed a pooled population PK analysis of ciprofloxacin after intravenous administration using individual patient data from three studies. Additionally, we studied the PK differences between these studies through a post-hoc analysis.

Methods

Individual patient data from three studies (study 1, 2, and 3) were pooled. The pooled data set consisted of 1094 ciprofloxacin concentration–time data points from 140 ICU patients. Nonlinear mixed-effects modeling was used to develop a population PK model. Covariates were selected following a stepwise covariate modeling procedure. To analyze PK differences between the three original studies, random samples were drawn from the posterior distribution of individual PK parameters. These samples were used for a simulation study comparing PK exposure and the percentage of target attainment between patients of these studies.

Results

A two-compartment model with first-order elimination best described the data. Inter-individual variability was added to the clearance, central volume, and peripheral volume. Inter-occasion variability was added to clearance only. Body weight was added to all parameters allometrically. Estimated glomerular filtration rate on ciprofloxacin clearance was identified as the only covariate relationship resulting in a drop in inter-individual variability of clearance from 58.7 to 47.2%. In the post-hoc analysis, clearance showed the highest deviation between the three studies with a coefficient of variation of 14.3% for posterior mean and 24.1% for posterior inter-individual variability. The simulation study showed that following the same dose regimen of 400 mg three times daily, the area under the concentration–time curve of study 3 was the highest with a mean area under the concentration–time curve at 24 h of 58 mg·h/L compared with that of 47.7 mg·h/L for study 1 and 47.6 mg·h/L for study 2. Similar differences were also observed in the percentage of target attainment, defined as the ratio of area under the concentration–time curve at 24 h and the minimum inhibitory concentration. At the epidemiological cut-off minimum inhibitory concentration of Pseudomonas aeruginosa of 0.5 mg/L, percentage of target attainment was only 21%, 18%, and 38% for study 1, 2, and 3, respectively.

Conclusions

We developed a population PK model of ciprofloxacin in ICU patients using pooled data of individual patients from three studies. A simple ciprofloxacin dose recommendation for the entire ICU population remains challenging owing to the PK differences within ICU patients, hence dose individualization may be needed for the optimization of ciprofloxacin treatment.

中文翻译：

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用于探索重症监护患者环丙沙星药代动力学变异性的汇总群体药代动力学分析

背景和目的

先前的环丙沙星在重症监护 (ICU) 患者中的药代动力学 (PK) 研究显示，估计的 PK 参数存在很大差异，表明需要对该人群进行进一步研究。因此，我们使用来自三项研究的个体患者数据对静脉注射后环丙沙星进行了汇总群体 PK 分析。此外，我们通过事后分析研究了这些研究之间的 PK 差异。

方法

汇总了三项研究（研究 1、2 和 3）的个体患者数据。汇总数据集包含来自 140 名 ICU 患者的 1094 个环丙沙星浓度-时间数据点。使用非线性混合效应模型来开发群体 PK 模型。按照逐步协变量建模程序选择协变量。为了分析三项原始研究之间的 PK 差异，从各个 PK 参数的后验分布中抽取了随机样本。这些样本用于模拟研究，比较这些研究的患者之间的 PK 暴露和目标实现百分比。

结果

具有一阶消除的两室模型最好地描述了数据。清除率、中心体积和外周体积增加了个体间差异。仅将场合间的变异性添加到清除率中。体重以异速生长方式添加到所有参数中。环丙沙星清除率的估计肾小球滤过率被确定为唯一的协变量关系，导致清除率的个体间变异性从 58.7% 下降至 47.2%。在事后分析中，清除率显示三项研究之间的偏差最高，后验平均值变异系数为 14.3%，后验个体间变异系数为 24.1%。模拟研究表明，在400 mg每日3次的相同剂量方案下，研究3的浓度-时间曲线下面积最高，24 h时的平均浓度-时间曲线下面积为58 mg·h/ L 与研究 1 的 47.7 mg·h/L 和研究 2 的 47.6 mg·h/L 进行比较。在目标实现百分比方面也观察到类似的差异，定义为浓度-时间曲线下面积比24 h 和最低抑菌浓度。在铜绿假单胞菌的流行病学截止最低抑制浓度为0.5 mg/L时，研究1、2和3的目标达到百分比分别仅为21%、18%和38%。

结论

我们利用三项研究中个体患者的汇总数据，开发了 ICU 患者中环丙沙星的群体 PK 模型。由于 ICU 患者内部的 PK 差异，针对整个 ICU 人群的简单环丙沙星剂量建议仍然具有挑战性，因此可能需要个体化剂量来优化环丙沙星治疗。