Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation To Describe the Pharmacodynamic Profile of Cefditoren in Plasma and Epithelial Lining Fluid
Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation To Describe the Pharmacodynamic Profile of Cefditoren in Plasma and Epithelial Lining Fluid
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使用群体药代动力学模型和蒙特卡罗模拟来描述血浆和上皮内衬液中头孢托伦的药效学特征
DOI：
10.1128/aac.00736-06
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发表时间：
2007
影响因子：
4.9
通讯作者：
F. Sörgel
中科院分区：
文献类型：
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作者：
T. Lodise;M. Kinzig‐Schippers;G. Drusano;U. Loos;F. Vogel;J. Bulitta;M. Hinder;F. Sörgel
摘要头孢妥仑是一种广谱口服头孢菌素，对包括耐多药肺炎链球菌在内的临床相关呼吸道病原体有很高的活性。本研究描述了其在血浆和上皮衬里液体(ELF)中的药效学特征。测定了24例患者禁食条件下的血浆和ELF药代动力学数据。用高效液相色谱-串联质谱法测定血浆和支气管肺泡灌洗液中的头孢妥仑和尿素浓度。在血浆和ELF中的浓度-时间分布由三个处理室和一级吸收、消除和转移模型模拟。药代动力学参数在群体药代动力学分析(大的非参数自适应网格与自适应γ)中确定。使用Adapt II程序对9999名受试者进行蒙特卡罗模拟，以估计在每12小时口服400 mg头孢妥仑的情况下，游离头孢妥仑血浆浓度(88%)、蛋白结合浓度和ELF总浓度在给药间隔的33%内超过MIC的目标实现概率。经过贝叶斯步骤后，模型与数据的总体拟合度良好，预测的血浆和ELF浓度与观测浓度的曲线图显示的斜率和截距分别非常接近理想值1.0和0.0。在血浆达到目标的概率分析中，对于0.06毫克/升的MIC，在给药间隔的33%内，实现游离或非结合血浆浓度超过生物体MIC的时间的概率为80%。与血浆相似，ELF中MIC为0.06 mg/L时，达到33%MIC以上的概率为80%。研究发现，当在血浆和ELF中禁食给药时，头孢妥仑对包括大多数对青霉素中等敏感的肺炎链球菌在内的MIC达到0.06毫克/升的抑菌效果的几率很低。
ABSTRACT Cefditoren is a broad-spectrum, oral cephalosporin that is highly active against clinically relevant respiratory tract pathogens, including multidrug-resistant Streptococcus pneumoniae. This study described its pharmacodynamic profile in plasma and epithelial lining fluid (ELF). Plasma and ELF pharmacokinetic data were obtained from 24 patients under fasting conditions. Cefditoren and urea concentrations were determined in plasma and bronchoalveolar lavage fluid by liquid chromatography-tandem mass spectrometry. Concentration-time profiles in plasma and ELF were modeled using a model with three disposition compartments and first-order absorption, elimination, and transfer. Pharmacokinetic parameters were identified in a population pharmacokinetic analysis (big nonparametric adaptive grid with adaptive γ). Monte Carlo simulation (9,999 subjects) was performed with the ADAPT II program to estimate the probability of target attainment at which the free-cefditoren plasma concentrations (88%) protein binding and total ELF concentrations exceeded the MIC for 33% of the dosing interval for 400 mg cefditoren given orally every 12 h. After the Bayesian step, the overall fits of the model to the data were good, and plots of predicted versus observed concentrations for plasma and ELF showed slopes and intercepts very close to the ideal values of 1.0 and 0.0, respectively. In the plasma probability of target attainment analysis, the probability of achieving a time for which free, or unbound, plasma concentration exceeds the MIC of the organism for 33% of the dosing interval was <80% for a MIC of >0.06 mg/liter. Similar to plasma, the probability of achieving a time above the MIC of 33% was <80% for MIC of >0.06 mg/liter in ELF. Cefditoren was found to have a low probability of achieving a bacteriostatic effect against MICs of >0.06 mg/liter, which includes most S. pneumoniae isolates with intermediate susceptibility to penicillin, when given in the fasting state in both plasma and ELF.
DOI：
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发表时间：
1990
期刊：
The American review of respiratory disease
影响因子：
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作者：
通讯作者：
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