Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients
Early bactericidal activity of delamanid (OPC-67683) in smear-positive pulmonary tuberculosis patients
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DOI：
10.5588/ijtld.10.0616
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发表时间：
2011-07-01
影响因子：
4
通讯作者：
Donald, P. R.
中科院分区：
文献类型：
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作者：
Diacon, A. H.;Dawson, R.;Donald, P. R.
背景技术背景：Delamanid（OPC-67683）是一种新的分枝杆菌酸生物合成抑制剂，在低的最低抑菌浓度下对结核分枝杆菌有活性。（63%男性; 54.7 +/- 9.9 kg; 30.7 +/- 10.8岁）被随机分配接受delamanid 100、200、300或400 mg每日给药14天。M.在琼脂平板上从过夜痰收集中计数结核菌，以计算早期杀菌活性（EBA），定义为log（10）cfu/ml痰/天的下降。但是，在此情况下，接受200 mg（70%）和300 mg（80%）的患者在14天内痰量下降≥ 0.9 log（10）cfu/ml的应答率高于接受100 mg（45%）的患者400 mg（27%）。从第2天开始，所有剂量组合的平均EBA（0.040 +/- 0.056 log（10）cfu/ml痰液/天）具有显著性。Delamanid暴露量低于剂量比例，在300 mg时达到平台，可能是由于剂量限制性吸收。中度，但显着的相关性，发现C，和EBA之间，表明暴露依赖。Delamanid耐受性良好，无显着toxics.CONCLUSIONS：Delamanid在所有剂量是安全的，耐受性良好，并表现出显着的依赖性EBA超过14天，支持其药代动力学和抗结核活性的进一步调查。
BACKGROUND: Delamanid (OPC-67683) is a novel mycolic acid biosynthesis inhibitor active against Mycobacterium tuberculosis at a low minimum inhibitory concentration.METHODS: Forty-eight patients with smear-positive tuberculosis (63% male; 54.7 +/- 9.9 kg; 30.7 +/- 10.8 years) were randomly assigned to receive delamanid 100, 200, 300 or 400 mg daily for 14 days. Colony forming units (cfu) of M. tuberculosis were counted on agar plates from overnight sputum collections to calculate early bactericidal activity (EBA), defined as fall in log(10) cfu/ml sputum/day.RESULTS: The EBA of delamanid was monophasic and not significantly different between dosages; however, more patients receiving 200 mg (70%) and 300 mg (80%) experienced a response of >= 0.9 log(10) cfu/ml sputum decline over 14 days than those receiving 100 mg (45%) and 400 mg (27%). The average EBA of all dosages combined (0.040 +/- 0.056 log(10) cfu/ml sputum/day) was significant from day 2 onward. Delamanid exposure was less than dosage-proportional, reaching a plateau at 300 mg, likely due to dose-limited absorption. Moderate but significant correlation was found between C,, and EBA, indicating exposure dependence. Delamanid was well tolerated without significant toxicity.CONCLUSIONS: Delamanid at all dosages was safe, well tolerated and demonstrated significant exposure-dependent EBA over 14 days, supporting further investigation of its pharmacokinetics and anti-tuberculosis activity.