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首页> 外文期刊>Antimicrobial agents and chemotherapy. >PA-824 exhibits time-dependent activity in a murine model of tuberculosis.
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PA-824 exhibits time-dependent activity in a murine model of tuberculosis.

机译：PA-824在结核病鼠模型中表现出时间依赖性活性。

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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.
机译：PA-824是用于治疗肺结核的II期临床试验中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作用。在患有结核病的人中，PA-824在每天200至1,200 mg的剂量范围内表现出早期杀菌活性（EBA），但未观察到剂量反应作用。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级研究。剂量范围的药代动力学数据用于模拟药物暴露情况。从结核分枝杆菌气溶胶感染后2周开始，在24天内分3、4、8、12、24或48个分剂量分别服用144至4,608 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）密切相关，并且与游离药物AUC / MIC（R（2）= 0.60）相关，但与游离药物C无关（max）/ MIC（R（2）= 0.17），其中T（> MIC）是在稳态药代动力学条件下药物浓度超过MIC的给药间隔的累计百分比，而AUC是在以下浓度下的面积-时间曲线。当数据集仅限于给药间隔为 MIC）和AUC / MIC值都很好地适合了数据。游离药物T（> MIC）为22、48和77％分别与抑菌，1-log杀灭和1.59-log杀灭有关（或观察到的最大作用的80％）。基于I期数据的人体药效​​学模拟预测，每天200 mg / kg的游离药物T（> MIC）值接近目标值，以实现最大的杀菌效果。结果支持最近证明的EBA为200 mg /天，并且缺乏200至1,200 mg /天的剂量反应。 T（> MIC）与AUC / MIC一起是PA-824剂量优化的基础参数。

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