PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis
PA-824 Exhibits Time-Dependent Activity in a Murine Model of Tuberculosis
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DOI：
10.1128/aac.00849-10
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发表时间：
2011-01-01
影响因子：
4.9
通讯作者：
Nuermberger, Eric L.
中科院分区：
文献类型：
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作者：
Ahmad, Zahoor;Peloquin, Charles A.;Nuermberger, Eric L.
PA-824是正在进行II期临床试验的两种硝基咪唑之一。在小鼠中，它具有剂量依赖性的早期杀菌和灭菌活性。在结核病患者中，PA-824在每天200至1200毫克剂量范围内显示出早期杀菌活性（EBA），但未观察到剂量-反应效应。为了更好地了解药物暴露与效果之间的关系，我们在小鼠中进行了剂量分离研究。剂量范围内的药代动力学数据用于模拟药物暴露概况。从气溶胶感染结核分枝杆菌后2周开始，在24天内分3、4、8、12、24或48次给药144至4608 mg/kg的PA-824总剂量。治疗后肺CFU计数与游离药物T->MIC （R-2 = 0.87）和游离药物AUC/MIC （R-2 = 0.60）呈强相关，但与游离药物C-max/MIC不相关（R-2 = 0.17），其中T->MIC为稳态药代动力学条件下药物浓度超过MIC的给药间隔累积百分比，AUC为浓度-时间曲线下面积。当数据集仅限于MIC给药间隔的方案时，AUC/MIC值与数据吻合良好。游离药物T->MIC分别为22、48和77%，与抑菌作用、1对数杀伤和1.59对数杀伤（或最大观察效果的80%）相关。基于I期数据的人体药效学模拟预测，200 mg/天产生的游离药物T->MIC值接近观察到的最大抗菌效果目标。结果支持最近证明的EBA为200毫克/天，并且在200至1200毫克/天之间缺乏剂量反应。T->MIC与AUC/MIC是PA-824剂量优化的基础参数。
PA-824 is one of two nitroimidazoles in phase II clinical trials to treat tuberculosis. In mice, it has dose-dependent early bactericidal and sterilizing activity. In humans with tuberculosis, PA-824 demonstrated early bactericidal activity (EBA) at doses ranging from 200 to 1,200 mg per day, but no dose-response effect was observed. To better understand the relationship between drug exposure and effect, we performed a dose fractionation study in mice. Dose-ranging pharmacokinetic data were used to simulate drug exposure profiles. Beginning 2 weeks after aerosol infection with Mycobacterium tuberculosis, total PA-824 doses from 144 to 4,608 mg/kg were administered as 3, 4, 8, 12, 24, or 48 divided doses over 24 days. Lung CFU counts after treatment were strongly correlated with the free drug T->MIC (R-2 = 0.87) and correlated with the free drug AUC/MIC (R-2 = 0.60), but not with the free drug C-max/MIC (R-2 = 0.17), where T->MIC is the cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions and AUC is the area under the concentration-time curve. When the data set was limited to regimens with dosing intervals of MIC and the AUC/MIC values fit the data well. Free drug T->MIC of 22, 48, and 77% were associated with bacteriostasis, a 1-log kill, and a 1.59-log kill (or 80% of the maximum observed effect), respectively. Human pharmacodynamic simulations based on phase I data predict 200 mg/day produces free drug T->MIC values near the target for maximal observed bactericidal effect. The results support the recently demonstrated an EBA of 200 mg/day and the lack of a dose-response between 200 and 1,200 mg/day. T->MIC, in conjunction with AUC/MIC, is the parameter on which dose optimization of PA-824 should be based.