TY -的T1 -杀菌活动增加dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin JF - European Respiratory Journal JO - Eur Respir J DO - 10.1183/13993003.00955-2020 VL - 58 IS - 1 SP - 2000955 AU - te Brake, Lindsey H.M. AU - de Jager, Veronique AU - Narunsky, Kim AU - Vanker, Naadira AU - Svensson, Elin M. AU - Phillips, Patrick P.J. AU - Gillespie, Stephen H. AU - Heinrich, Norbert AU - Hoelscher, Michael AU - Dawson, Rodney AU - Diacon, Andreas H. AU - Aarnoutse, Rob E. AU - Boeree, Martin J. Y1 - 2021/07/01 UR - //www.qdcxjkg.com/content/58/1/2000955.abstract N2 - 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 ER -