Jalusic Kris Oliver, Hempel Georg, Arnemann Philip-Helge, Spiekermann Christina, Kampmeier Tim-Gerald, Ertmer Christian, Gastine Silke, Hessler Michael
Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Muenster, Muenster, Germany.
Institute of Epidemiology and Social Medicine, Faculty of Medicine, University of Muenster, Muenster, Germany.
Br J Clin Pharmacol. 2021 Jun;87(6):2502-2510. doi: 10.1111/bcp.14657. Epub 2020 Dec 13.
To determine the distribution of vancomycin into the cerebrospinal fluid (CSF) in patients with external ventricular drain (EVD)-associated ventriculitis, the pharmacokinetics of vancomycin were evaluated and covariate relationships explored.
For the population pharmacokinetic model patients were recruited in a neurocritical care unit at the University Hospital of Muenster in the period between January 2014 and June 2015. All patients had a clinical evidence of EVD-associated ventriculitis. Population pharmacokinetic analysis of vancomycin was performed using NONMEM.
A total of 184 blood and 133 CSF samples were collected from 29 patients. The final population pharmacokinetic model is a three-compartment model with linear elimination. Creatinine clearance (Cl ) and CSF-lactate were detected as significant covariates, showing that the total vancomycin plasma clearance (Cl) depends on Cl and furthermore the clearance (Cl ) between the central and CSF compartment correlates with CSF lactate concentration. Based on the final model, the following values were estimated by NONMEM: Cl = 5.15 L/h, Q (intercompartmental clearance) = 3.31 L/h, Cl = 0.0031 L/h, V = 42.1 L, V = 0.32 L and the value of V was fixed to 86.2 L. With the developed pharmacokinetic model, area under the curve (AUC) values as well as CSF trough levels were simulated.
Based on our analysis, the dosing of vancomycin should be referred to the degree of inflammation (derived from the CSF lactate concentration) and renal function (derived from Cl ).
为了确定万古霉素在伴有外部脑室引流（EVD）相关性脑室炎患者脑脊液（CSF）中的分布情况，我们评估了万古霉素的药代动力学并探讨了协变量关系。
2014年1月至2015年6月期间，在明斯特大学医院的神经重症监护病房招募了用于群体药代动力学模型研究的患者。所有患者均有EVD相关性脑室炎的临床证据。使用NONMEM对万古霉素进行群体药代动力学分析。
共收集了29例患者的184份血液样本和133份脑脊液样本。最终的群体药代动力学模型是一个具有线性消除的三室模型。肌酐清除率（Cl）和脑脊液乳酸盐被检测为显著协变量，表明万古霉素的总血浆清除率（Cl）取决于Cl，此外，中央室与脑脊液室之间的清除率（Cl）与脑脊液乳酸盐浓度相关。基于最终模型，NONMEM估计了以下值：Cl = 5.15 L/h，Q（室间清除率）= 3.31 L/h，Cl = 0.0031 L/h，V = 42.1 L，V = 0.32 L，V的值固定为86.2 L。利用所建立的药代动力学模型，模拟了曲线下面积（AUC）值以及脑脊液谷浓度。
基于我们的分析，万古霉素的给药应参考炎症程度（由脑脊液乳酸盐浓度得出）和肾功能（由Cl得出）。
