Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients
Early Bactericidal Activity and Pharmacokinetics of PA-824 in Smear-Positive Tuberculosis Patients
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DOI：
10.1128/aac.01354-09
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发表时间：
2010-08-01
影响因子：
4.9
通讯作者：
Spigelman, Melvin K.
中科院分区：
文献类型：
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作者：
Diacon, Andreas H.;Dawson, Rodney;Spigelman, Melvin K.
PA-824是一种新型硝基咪唑并恶嗪，正在评估其改善结核病（TB）治疗的潜力。这项随机研究评价了PA-824在药物敏感、痰涂片阳性成人肺结核患者中的安全性、耐受性、药代动力学和延长早期杀菌活性。每个队列15例患者接受4种口服PA-824剂量之一：200、600、1，000或1，200 mg/天，持续14天。8例受试者接受每日1次标准抗结核治疗作为阳性对照。主要疗效终点为连续过夜痰液采集的琼脂平板上培养的痰液中结核分枝杆菌对数CFU的平均变化率，表示为log（10）CFU/天/ml（+/-标准差[SD]）。在每日200 - 1，000 mg剂量范围内，药物显示血清浓度呈剂量线性增加，但低于剂量比例。与每日1，000 mg相比，1，200 mg剂量未产生额外暴露。标准处理下的平均每日CFU下降为0.148（+/- 0.055），与先前研究中发现的一致。PA-824下的平均每日下降为0.098（+/- 0.072），所有四种剂量均相当。PA-824似乎安全且耐受性良好;可能与PA-824相关的不良事件发生率似乎与剂量相关。我们得出结论，PA-824在200至1，200 mg每日剂量范围内表现出杀菌活性，持续14天。由于在最低剂量下意外地达到了最大功效，因此现在应探索较低剂量的活性。
PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml (+/- standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/- 0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/- 0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.