PT -期刊文章AU - te刹车,林赛•莫莱森盟- de Jager薇罗尼卡非盟- Narunsky金盟——万科Naadira AU -斯文森,艾琳m . AU -菲利普斯,帕特里克P.J. AU - Gillespie,斯蒂芬·h·盟——海因里希,Norbert AU -霍尔舍,迈克尔AU -道森,罗德尼AU -敏,安德烈亚斯h . AU - Aarnoutse罗伯•e . AU - Boeree马丁j . TI -杀菌活动增加但dose-limiting难耐50 mg·公斤<一口>−1 < / >共舞,利福平援助- 10.1183/13993003.00955 -2020 DP - 2021年7月01 TA -欧洲呼吸杂志》第六PG - 2000955 - 58 //www.qdcxjkg.com/content/58/1/2000955.short的IP - 1 4099 - 4100 //www.qdcxjkg.com/content/58/1/2000955.fullSO - Eur respirj2021 7月01日;背景越来越多的数据表明，高剂量的利福平更有效，并缩短结核病(TB)治疗时间。本研究评估了增加剂量利福平的安全性、耐受性、药代动力学以及7天和14天早期杀菌活性(EBA)。在这里，我们报告PanACEA HIGHRIF1最终队列的结果，这是一项针对未接受治疗的成年涂片阳性结核病患者的剂量增加研究。方法患者连续接受40或50 mg·kg - 1利福平单药治疗(第1 - 7天)，并在第8 - 14天补充标准剂量异烟肼、吡嗪酰胺和乙胺丁醇。结果在40mg·kg - 1队列中(n=15)， 13例患者在单药治疗期间共发生36起不良事件，导致1例治疗中断。在50 mg·kg−1队列(n=17)中，所有患者在单药治疗期间发生不良事件，共有93例;11名患者退出或停止研究用药。不良事件多为轻度/中度和耐受性，而非安全性相关，如胃肠道紊乱、瘙痒、高胆红素血症和黄疸。 There was a more than proportional increase in the rifampicin geometric mean area under the plasma concentration–time curve from time 0 to 12 h (AUC0–24 h) for 50 mg·kg−1 compared with 40 mg·kg−1; 571 (range 320–995) versus 387 (range 201–847) mg·L−1·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg−1 (11% (range 8–17%)) was comparable with lower rifampicin doses. 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