Background Knowledge regarding CNS pharmacokinetics of moxifloxacin is limited, with unknown consequences for patients with meningitis caused by bacteria resistant to beta-lactams or caused by TB. Objective (i) To develop a novel porcine model for continuous investigation of moxifloxacin concentrations within brain extracellular fluid (ECF), CSF and plasma using microdialysis, and (ii) to compare these findings to the pharmacokinetic/pharmacodynamic (PK/PD) target against TB. Methods Six female pigs received an intravenous single dose of moxifloxacin (6 mg/kg) similar to the current oral treatment against TB. Subsequently, moxifloxacin concentrations were determined by microdialysis within five compartments: brain ECF (cortical and subcortical) and CSF (ventricular, cisternal and lumbar) for the following 8 hours. Data were compared to simultaneously obtained plasma samples. Chemical analysis was performed by high pressure liquid chromatography with mass spectrometry. The applied PK/PD target was defined as a maximum drug concentration (Cmax):MIC ratio >8. Results We present a novel porcine model for continuous in vivo CNS pharmacokinetics for moxifloxacin. Cmax and AUC0–8h within brain ECF were significantly lower compared to plasma and lumbar CSF, but insignificantly different compared to ventricular and cisternal CSF. Unbound Cmax:MIC ratio across all investigated compartments ranged from 1.9 to 4.3. Conclusion A single dose of weight-adjusted moxifloxacin administered intravenously did not achieve adequate target site concentrations within the uninflamed porcine brain ECF and CSF to reach the applied TB CNS target.

中文翻译：

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连续评估脑细胞外液、脑脊液和血浆中单剂量莫西沙星浓度：一种新型猪模型

背景知识 关于莫西沙星的中枢神经系统药代动力学知识有限，对于由 β-内酰胺耐药细菌引起或由结核病引起的脑膜炎患者的后果未知。目的 (i) 开发一种新型猪模型，利用微透析连续研究脑细胞外液 (ECF)、CSF 和血浆中的莫西沙星浓度，以及 (ii) 将这些结果与药代动力学/药效学 (PK/PD) 目标进行比较结核病。方法 六头母猪接受静脉单剂量莫西沙星（6 mg/kg），类似于目前的口服结核病治疗方法。随后，在接下来的 8 小时内，通过微透析测定五个区室中的莫西沙星浓度：脑 ECF（皮质和皮质下）和 CSF（脑室、脑池和腰椎）。将数据与同时获得的血浆样品进行比较。通过高压液相色谱法和质谱法进行化学分析。所应用的PK/PD目标被定义为最大药物浓度(Cmax):MIC比率＞8。结果我们提出了一种用于莫西沙星连续体内中枢神经系统药代动力学的新型猪模型。脑ECF内的Cmax和AUC0-8h显着低于血浆和腰椎CSF，但与心室和脑池CSF相比差异不显着。所有研究区室的未结合 Cmax:MIC 比率范围为 1.9 至 4.3。结论 单剂量静脉注射调整体重的莫西沙星未能在未发炎的猪脑 ECF 和 CSF 内达到足够的靶位点浓度，无法达到应用的结核病 CNS 目标。