Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis
Pharmacokinetics-pharmacodynamics of rifampin in an aerosol infection model of tuberculosis
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DOI：
10.1128/aac.47.7.2118-2124.2003
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发表时间：
2003-07-01
影响因子：
4.9
通讯作者：
Balasubramanian, V
中科院分区：
文献类型：
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作者：
Jayaram, R;Gaonkar, S;Balasubramanian, V
关于抗结核分枝杆菌药物的药代动力学（PK）-药效学（PD）关系的信息有限。我们的目的是根据体外和PK特性确定最能描述利福平疗效的PK-PD参数。通过平衡透析，与83.8%的蛋白结合率一致，M.结核菌株H37 Rv从无血清系统中的0.1上升到在50%血清存在下测试时的1.0mg/ml。在时间-杀灭研究中，利福平在体外表现出浓度-时间曲线下面积（AUC）依赖性杀灭作用，在所有日期均观察到最大杀灭作用，并且在9天暴露期内效价稳定增加。在巨噬细胞单层模型中对细胞内微生物进行的MIC和时间杀灭研究产生了相似的结果。通过使用6天内剂量范围和剂量分级的鼠气溶胶感染模型，发现与细菌计数减少最相关的PD参数为AUC/MIC（r（2）= 0.95），血清最大浓度/MIC（r（2）= 0.86）和维持在MIC以上的时间（r（2）= 0.44）显示出较小程度的相关性。
Limited information exists on the pharmacokinetic (PK)-pharmacodynamic (PD) relationships of drugs against Mycobacterium tuberculosis. Our aim was to identify the PK-PD parameter that best describes the efficacy of rifampin on the basis of in vitro and PK properties. Consistent with 83.8% protein binding by equilibrium dialysis, the rifampin MIC for M. tuberculosis strain H37Rv rose from 0.1 in a serum-free system to 1.0 mg/ml when it was tested in the presence of 50% serum. In time-kill studies, rifampin exhibited area under the concentration-time curve (AUC)-dependent killing in vitro, with maximal killing seen on all days and with the potency increasing steadily over a 9-day exposure period. MIC and time-kill studies performed with intracellular organisms in a macrophage monolayer model yielded similar results. By use of a murine aerosol infection model with dose ranging and dose fractionation over 6 days, the PD parameter that best correlated with a reduction in bacterial counts was found to be AUC/MIC (r(2) = 0.95), whereas the maximum concentration in serum/MIC (r(2) = 0.86) and the time that the concentration remained above the MIC (r(2) = 0.44) showed lesser degrees of correlation.