Li Xingang, Wu Yuanxing, Sun Shusen, Zhao Zhigang, Wang Qiang
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Precision Medicine Research Center for Neurological Disorders, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China.
Respiratory and Critical Care Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
J Pharm Sci. 2016 Nov;105(11):3425-3431. doi: 10.1016/j.xphs.2016.08.012. Epub 2016 Sep 23.
Our previous study indicates that cerebrospinal fluid (CSF) albumin level is a determinant of CSF vancomycin concentration for postoperative neurosurgical patients. We aimed to develop an improved vancomycin population pharmacokinetic model with incorporation of more covariates, and to provide dosing guidance for clinicians. Vancomycin was administered intravenously to 20 patients with external ventricular drains after neurosurgical operation. Blood and CSF were collected and vancomycin concentrations were measured by HPLC. A separate CSF compartment was considered, and was linked to the central compartment by a first-order process (Q). The clearance of the CSF compartment (Cl) was used to characterize vancomycin elimination from CSF through external ventricular drain. Nonlinear mixed-effects modeling approach was used to develop the model. The CSF albumin level (mg/dL) was the covariate influencing Q: Q=0.0049+0.000021×(CSF albumin-279). The effect of body weight (BW, kg) was significant on central volume (V): V=27.84+0.96×(BW-69). All parameters were estimated with an acceptable precision (relative standard error: RSE% < 30.26). The performance of the final model was acceptable with our previous dataset. A simple to use dosage regimen table was created to guide clinicians with vancomycin dosing. This model incorporates variables of both CSF albumin and BW, which offers improvements to the previous pharmacokinetics model.
我们之前的研究表明，脑脊液（CSF）白蛋白水平是神经外科术后患者脑脊液万古霉素浓度的一个决定因素。我们旨在开发一个纳入更多协变量的改进型万古霉素群体药代动力学模型，并为临床医生提供给药指导。对20例神经外科手术后带有脑室外引流管的患者静脉给予万古霉素。采集血液和脑脊液，采用高效液相色谱法测定万古霉素浓度。考虑了一个单独的脑脊液隔室，并通过一级过程（Q）与中央隔室相连。脑脊液隔室的清除率（Cl）用于表征万古霉素通过脑室外引流管从脑脊液中的消除情况。采用非线性混合效应建模方法建立模型。脑脊液白蛋白水平（mg/dL）是影响Q的协变量：Q = 0.0049 + 0.000021×（脑脊液白蛋白 - 279）。体重（BW，kg）对中央室容积（V）有显著影响：V = 27.84 + 0.96×（BW - 69）。所有参数的估计精度均可接受（相对标准误差：RSE% < 30.26）。最终模型在我们之前的数据集上表现可接受。创建了一个易于使用的给药方案表，以指导临床医生进行万古霉素给药。该模型纳入了脑脊液白蛋白和体重这两个变量，对之前的药代动力学模型进行了改进。
