RT轴颈文章SR电子T1增加了杀菌活性，但剂量限制在50 mg·kg^-1利福平jf欧洲呼吸杂志Jo EUR Respir J FD欧洲呼吸道学会SP 2000955 Do 10.1183 / 13188bet官网地址993003.00955-2020 VO 58是1 A1 Te Brake，Lindsey H.M.A1 de Jager, Veronique A1 Narunsky, Kim A1 Vanker, Naadira A1 Svensson, Elin M. A1 Phillips, Patrick P.J. A1 Gillespie, Stephen H. A1 Heinrich, Norbert A1 Hoelscher, Michael A1 Dawson, Rodney A1 Diacon, Andreas H. A1 Aarnoutse, Rob E. A1 Boeree, Martin J. YR 2021 UL //www.qdcxjkg.com/content/58/1/2000955.abstract AB Background Accumulating data indicate that higher rifampicin doses are more effective and shorten tuberculosis (TB) treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 7- and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Here we report the results of the final cohorts of PanACEA HIGHRIF1, a dose escalation study in treatment-naive adult smear-positive patients with TB.Methods Patients received, in consecutive cohorts, 40 or 50 mg·kg−1 rifampicin once daily in monotherapy (day 1–7), supplemented with standard dose isoniazid, pyrazinamide and ethambutol between days 8 and 14.Results In the 40 mg·kg−1 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg−1 cohort (n=17), all patients experienced adverse events during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. Adverse events were mostly mild/moderate and tolerability rather than safety related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinaemia and jaundice. 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