Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.
Making the case for precision dosing: visualizing the variability of cefepime exposures in critically ill adults.
复制标题
论证精确给药：可视化危重成人头孢吡肟暴露的变异性。
DOI：
10.1093/jac/dkad211
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Scheetz,MarcH
中科院分区：
文献类型：
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作者：
Chang,Jack;Liu,Jiajun;Alshaer,MohammadH;Venugopalan,Veena;Maranchick,Nicole;Peloquin,CharlesA;Rhodes,NathanielJ;Scheetz,MarcH
目的调查和描述的变异性头孢吡肟暴露之间的“现实世界”，重症患者通过使用人口药代动力学建模和模拟，并与翻译这些研究结果visualization.MethodsA队列的成人医疗ICU患者谁接受头孢吡肟与治疗药物监测进行了研究。开发了两室模型，以估计头孢吡肟清除率（模型1）并模拟1000例患者的头孢吡肟暴露量，每例患者的肌酐清除率均为60 mL/min，每8小时接受1 g头孢吡肟静脉注射30分钟（模型2）。头孢吡肟清除率和肌酐清除率（CrCL）之间的关系的变化是可视化的，和一个随机的，有代表性的样本10个模拟患者被用来说明头孢吡肟exposs.ResultsA的变化，共75个成人医疗ICU患者（52%的女性）和98个血清头孢吡肟样本被列入研究。头孢吡肟的群体参数估计值在模型1中显示出广泛的变异（CV：45%至95%），在个体水平0.226 mg/L时偏倚较低，但在群体模型10.6 mg/L时偏倚较高。模型2显示了相似的拟合，表明个体患者肌酐清除率校正略微改善了群体模型的偏倚（偏倚= 4.31 mg/L）。 在10个模拟的患者，临床医生会认为类似的从剂量的角度来看（即等效肌酐清除率），最大浓度后三个模拟剂量变化超过8倍，从41.2至339 mg/L，在第5和第95次的cefeles，清除率曲线是高度不同的。ICU患者中头孢吡肟的暴露量存在很大差异，即使是肾功能估计值相似的患者。目前仅基于肌酐清除率的人群调整方案将导致非预期的高暴露和低暴露，分别导致安全性和有效性问题。
ObjectiveTo investigate and describe the variability in cefepime exposures among ‘real-world’, critically ill patients by using population pharmacokinetic modelling and simulations, and with translation of these findings to visualizations.MethodsA cohort of adult medical ICU patients who received cefepime with therapeutic drug monitoring was studied. Two compartment models were developed to estimate cefepime clearance (Model 1) and simulate cefepime exposures among 1000 patients, each with identical creatinine clearance of 60 mL/min and receiving a regimen of cefepime 1 gram IV over 30 minutes, every 8 hours (Model 2). Variability in the relationship between cefepime clearance and creatinine clearance (CrCL) was visualized, and a random, representative sample of 10 simulated patients was utilized to illustrate variability in cefepime exposures.ResultsA total of 75 adult medical ICU patients (52% female) and 98 serum cefepime samples were included in the study. Population parameter estimates for cefepime displayed a wide range of variation in Model 1 (CV: 45% to 95%), with low bias at the individual level at 0.226 mg/L but high bias in the population model 10.6 mg/L. Model 2 displayed similar fits, demonstrating that correcting for individual patient creatinine clearance slightly improves the bias of the population model (bias = 4.31 mg/L). Among 10 simulated patients that a clinician would deem similar from a dosing perspective (i.e. equivalent creatinine clearance), maximum concentrations after three simulated doses varied more than 8-fold from 41.2 to 339 mg/L at the 5th and 95th percentiles, and clearance profiles were highly different.ConclusionCreatinine clearance estimates alone are inadequate for predicting cefepime exposures. Wide variations in cefepime exposure exist among ICU patients, even for those with similar kidney function estimates. Current population adjustment schemes based solely on creatinine clearance will result in unintended high and low exposures leading to safety and efficacy concerns, respectively.