Rustomjee R, Diacon A H, Allen J, Venter A, Reddy C, Patientia R F, Mthiyane T C P, De Marez T, van Heeswijk R, Kerstens R, Koul A, De Beule K, Donald P R, McNeeley D F
Unit for Clinical and Biomedical Tuberculosis Research, Medical Research Council, Durban, South Africa.
Antimicrob Agents Chemother. 2008 Aug;52(8):2831-5. doi: 10.1128/AAC.01204-07. Epub 2008 May 27.
Tibotec Medicinal Compound 207 (TMC207) is a novel diarylquinoline with a unique mode of action that targets mycobacterial ATP synthase. TMC207 exhibits high in vitro activity against mycobacterial strains either susceptible or resistant to all first-line and many second-line drugs, including fluoroquinolones, and has shown exceptional in vivo activity against several mycobacterial species in different animal models. In this early bactericidal activity study, 75 treatment-naïve patients with smear-positive pulmonary tuberculosis were randomized to once-daily oral TMC207 (25 mg, 100 mg, or 400 mg), 600 mg rifampin (RIF), or 300 mg isoniazid (INH) for 7 days. Sixteen-hour overnight sputum collected at baseline and on each treatment day was plated in serial dilutions on selective agar plates. The bactericidal activity was expressed as the log(10) decrease in CFU/ml sputum/day. Pharmacokinetic sampling was performed on day 7 of TMC207 administration up to 24 h postdose. The decreases in log(10) CFU counts (+/- standard deviation) from baseline to day 7 were 0.04 +/- 0.46 for 25 mg TMC207 (n = 14), 0.26 +/- 0.64 for 100 mg TMC207 (n = 14), 0.77 +/- 0.58 for 400 mg TMC207 (n = 14), 1.88 +/- 0.74 for INH (n = 11), and 1.70 +/- 0.71 for RIF (n = 14). Significant bactericidal activity of 400 mg TMC207 was observed from day 4 onward and was similar in magnitude to those of INH and RIF over the same period. The pharmacokinetics of TMC207 were linear across the dose range. In summary, TMC207 demonstrated bactericidal activity with a delayed onset and was well tolerated, and no study drug-related serious adverse events occurred.
替比泰克药用化合物207（TMC207）是一种新型二芳基喹啉，具有独特的作用模式，靶向分枝杆菌ATP合酶。TMC207对所有一线和许多二线药物（包括氟喹诺酮类）敏感或耐药的分枝杆菌菌株均表现出高体外活性，并且在不同动物模型中对几种分枝杆菌物种显示出卓越的体内活性。在这项早期杀菌活性研究中，75例初治涂片阳性肺结核患者被随机分为每日一次口服TMC207（25毫克、100毫克或400毫克）、600毫克利福平（RIF）或300毫克异烟肼（INH），疗程7天。在基线和每个治疗日收集的16小时过夜痰液进行系列稀释后接种在选择性琼脂平板上。杀菌活性以每毫升痰液中CFU/天的log(10)下降表示。在TMC207给药第7天直至给药后24小时进行药代动力学采样。从基线到第7天，log(10)CFU计数（±标准差）的下降情况为：25毫克TMC207组为0.04±0.46（n = 14），100毫克TMC207组为0.26±0.64（n = 14），400毫克TMC207组为0.77±0.58（n = 14），INH组为1.88±0.74（n = 11），RIF组为1.70±0.71（n = 14）。从第4天起观察到400毫克TMC207具有显著杀菌活性，且在同一时期其活性强度与INH和RIF相似。TMC207的药代动力学在整个剂量范围内呈线性。总之，TMC207表现出延迟起效的杀菌活性，耐受性良好，且未发生与研究药物相关的严重不良事件。
