Ghent University Hospital, Department of Critical Care Medicine, C. Heymanslaan 10, 9000 Ghent, Belgium.
University of Groningen, University Medical Center Groningen, Department of Anesthesiology, Groningen, The Netherlands; Ghent University, Laboratory of Medical Biochemistry and Clinical Analysis, Ghent, Belgium.
Int J Antimicrob Agents. 2019 Dec;54(6):741-749. doi: 10.1016/j.ijantimicag.2019.08.024. Epub 2019 Aug 31.
The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (V) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (K) and the maximum elimination rate for Michaelis-Menten elimination (V) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for K and V were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for K lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients.
本研究旨在评估危重症成年患者哌拉西林消除的饱和情况。17 例危重症成年患者接受了哌拉西林/他唑巴坦的连续和间歇性输注。采用群体药代动力学（PopPK）模型分析哌拉西林血浆浓度（n=217）。进行事后模拟以评估与该研究相关的Ⅰ类错误率。使用未见数据验证最终模型。平均误差（ME）和均方根误差（RMSE）分别作为偏差和不精确性的度量。具有平行线性和非线性消除的 PopPK 模型最适合数据。模型参数药物清除率（CL）、中央隔室体积（V）、外周隔室体积（V）和隔室间清除率（Q）的中位数和 95%置信区间（CI）分别为 9（7.69-11）L/h、6.18（4.93-11.2）L、11.17（7.26-12）L 和 15.61（12.66-23.8）L/h。Michaelis-Menten 常数（K）和 Michaelis-Menten 消除的最大消除率（V）在模型中没有人群变异性的估计，以避免过度拟合和Ⅰ类错误率的膨胀。K 和 V 的群体估计值分别为 37.09mg/L 和 353.57mg/h。偏倚（ME）为-20.8（95%CI-26.2 至-15.4）mg/L，而不精确性（RMSE）为 49.2（95%CI41.2-56）mg/L。总之，哌拉西林的消除是（部分）饱和的。此外，K 的人群估计值在治疗窗内，因此在为危重症患者定义哌拉西林最佳给药方案时，应考虑消除的饱和。
