% 0期刊文章% te刹车,林赛莫莱森% de Jager,薇罗尼卡% Narunsky,金正日%万科,Naadira % Svensson,艾琳·m·菲利普斯%,帕特里克P.J. % Gillespie,斯蒂芬·h·%海因里希,诺伯特•霍尔舍%,迈克尔%道森,罗德尼%敏,安德烈亚斯·h·% Aarnoutse,罗伯·e·% Boeree,马丁j . % T杀菌活动增加但dose-limiting难耐50 mg·公斤⁻¹利福平2021% % D J R 10.1183/13993003.00955 -2020%欧洲呼吸杂志% P 2000955 % V 58% N 1% X背景积累数据显示,利福平高剂量更有效和持续时间缩短结核病(TB)治疗。本研究评估安全、耐受性、药物动力学、7 - 14天早期杀菌活动(EBA)增加剂量的利福平。在这里,我们报告的结果最终灵丹妙药HIGHRIF1军团,在首次治疗成人剂量升级研究痰检阳性结核病患者。方法患者接受,在连续的军团,40或50 mg·公斤−1利福平在单一治疗(1 - 7天)每天一次,补充与标准剂量异烟肼、吡嗪酰胺和乙胺丁醇8和14天之间。导致40毫克·公斤−1组(n = 15), 13个病人经历了36单药治疗期间不良事件,导致一个治疗停药。在50 mg·公斤−1组(n = 17),所有患者不良事件单药治疗期间,总共93;11名患者退出研究药物或停止。不良事件主要是轻度或中度和耐受性而非安全相关,如胃肠道功能紊乱,瘙痒,hyperbilirubinaemia和黄疸。利福平有超过比例的增加几何平均血浆浓度时间曲线下的面积从时间0到12 h (AUC0-24 h) 50 mg·公斤−1与40毫克·公斤−1;571(范围320 - 995年)和387(范围201 - 847)mg·h·L−1,而峰值接触看到比例增加。Protein-unbound曝光后50 mg·公斤−1(11%(8 - 17%范围))是类似的利福平剂量较低。 Rifampicin exposures and bilirubin concentrations were correlated (Spearman's ρ=0.670 on day 3, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg−1: 14-day EBA −0.427 (95% CI −0.500– −0.355) log10CFU·mL−1·day−1.Conclusion Although associated with an increased bactericidal effect, the 50 mg·kg−1 dose was not well tolerated. Rifampicin at 40 mg·kg−1 was well tolerated and therefore selected for evaluation in a phase IIc treatment-shortening trial.While bactericidal activity continues to increase with dose, for the first time we identified dose-limiting intolerability for rifampicin dosed at 50 mg·kg−1; 40 mg·kg−1 seems the optimal tolerable dose for evaluation in TB treatment-shortening trials https://bit.ly/37dUIuB %U //www.qdcxjkg.com/content/erj/58/1/2000955.full.pdf