Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis.
Pharmacokinetics-pharmacodynamics analysis of bicyclic 4-nitroimidazole analogs in a murine model of tuberculosis.
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DOI：
10.1371/journal.pone.0105222
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Manjunatha UH
中科院分区：
文献类型：
--
作者：
Lakshminarayana SB;Boshoff HI;Cherian J;Ravindran S;Goh A;Jiricek J;Nanjundappa M;Nayyar A;Gurumurthy M;Singh R;Dick T;Blasco F;Barry CE 3rd;Ho PC;Manjunatha UH
PA-824是一种双环4-硝基咪唑，目前正在进行治疗结核病的II期临床试验。小鼠剂量分级药动学-药效学研究表明，PA-824体内药效的驱动因素是血浆中游离药物浓度高于MIC的时间（f> MIC）。在这项研究中，一组密切相关的强效双环4-硝基咪唑在体内PK和功效研究中进行了分析。在已建立的小鼠结核病模型中，与未治疗的对照组相比，不同硝基咪唑类似物的疗效在0.5至2.3 log CFU减少之间。此外，对7种硝基咪唑类似物进行了回顾性分析，以确定与体内疗效相关的PK参数。我们的研究结果表明，4-硝基咪唑类双环类药物的体内药效与肺PK的相关性优于与血浆PK的相关性。此外，具有中高分布体积和肺血浆比>2的硝基咪唑类似物具有良好的疗效。在所有PK-PD指标中，肺总T>MIC与体内疗效相关性最好（rs = 0.88），其次是肺Cmax/MIC和AUC/MIC。因此，肺部药物分布研究可以潜在地用于指导药效研究的化合物选择，从而加速寻找新的硝基咪唑类似物的药物发现工作。
PA-824 is a bicyclic 4-nitroimidazole, currently in phase II clinical trials for the treatment of tuberculosis. Dose fractionation pharmacokinetic-pharmacodynamic studies in mice indicated that the driver of PA-824 in vivo efficacy is the time during which the free drug concentrations in plasma are above the MIC (fT>MIC). In this study, a panel of closely related potent bicyclic 4-nitroimidazoles was profiled in both in vivo PK and efficacy studies. In an established murine TB model, the efficacy of diverse nitroimidazole analogs ranged between 0.5 and 2.3 log CFU reduction compared to untreated controls. Further, a retrospective analysis was performed for a set of seven nitroimidazole analogs to identify the PK parameters that correlate with in vivo efficacy. Our findings show that the in vivo efficacy of bicyclic 4-nitroimidazoles correlated better with lung PK than with plasma PK. Further, nitroimidazole analogs with moderate-to-high volume of distribution and Lung to plasma ratios of >2 showed good efficacy. Among all the PK-PD indices, total lung T>MIC correlated the best with in vivo efficacy (rs = 0.88) followed by lung Cmax/MIC and AUC/MIC. Thus, lung drug distribution studies could potentially be exploited to guide the selection of compounds for efficacy studies, thereby accelerating the drug discovery efforts in finding new nitroimidazole analogs.
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