Li Xingang, Sun Shusen, Wang Qiang, Zhao Zhigang
Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China.
College of Pharmacy, Western New England University, Springfield, MA, 01119, USA.
Eur J Drug Metab Pharmacokinet. 2018 Feb;43(1):45-53. doi: 10.1007/s13318-017-0422-1.
For patients with intracranial infection, local intrathecal administration of meropenem may be a useful method to obtain a sufficient drug concentration in the cerebral spinal fluid (CSF). However, a large inter-individual variability may pose treatment efficacy at risk. This study aimed to identify factors affecting drug concentration in the CSF using population pharmacokinetics method.
After craniotomy, aneurysm patients with an indwelling lumbar cistern drainage tube who received a combined intravenous and intrathecal administration of meropenem for the treatment of suspected intracranial infection were enrolled. Venous blood and CSF specimens were collected for determining meropenem concentrations. Nonlinear mixed-effects modeling method was used to fit blood and CSF concentrations simultaneously and to develop the population pharmacokinetic model. The proposed model was applied to simulate dosage regimens.
A three-compartmental model was established to describe meropenem in vivo behavior. Lumbar CSF drainage resulted in a drug loss, and drug clearance in CSF (CL) was employed to describe this. The covariate analysis found that the drainage volume (mL/day) was strongly associated with CL, and the effect of creatinine clearance was significant on the clearance of meropenem in blood (CL). Visual predictive check suggested that the proposed pharmacokinetic model agreed well with the observations. Simulation showed that both intravenous and intrathecal doses should be increased with the increases of minimum inhibitory concentration and daily CSF drainage volume.
This model incorporates covariates of the creatinine clearance and the drainage volume, and a simple to use dosage regimen table was created to guide clinicians with meropenem dosing.
对于颅内感染患者，局部鞘内注射美罗培南可能是在脑脊液（CSF）中获得足够药物浓度的一种有效方法。然而，个体间的巨大差异可能会影响治疗效果。本研究旨在使用群体药代动力学方法确定影响脑脊液中药物浓度的因素。
纳入开颅术后留置腰大池引流管、接受静脉和鞘内联合注射美罗培南治疗疑似颅内感染的动脉瘤患者。采集静脉血和脑脊液样本以测定美罗培南浓度。采用非线性混合效应建模方法同时拟合血液和脑脊液浓度，并建立群体药代动力学模型。应用所提出的模型模拟给药方案。
建立了一个三室模型来描述美罗培南的体内行为。腰大池脑脊液引流导致药物损失，采用脑脊液中的药物清除率（CL）来描述这一情况。协变量分析发现，引流量（毫升/天）与CL密切相关，肌酐清除率对美罗培南在血液中的清除率（CL）有显著影响。直观预测检查表明，所提出的药代动力学模型与观察结果吻合良好。模拟结果显示，静脉和鞘内给药剂量均应随着最低抑菌浓度和每日脑脊液引流量的增加而增加。
该模型纳入了肌酐清除率和引流量的协变量，并创建了一个易于使用的给药方案表，以指导临床医生使用美罗培南进行给药。
