RT Journal Article SR Electronic T1 Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg−1 rifampicin JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 2000955 DO 10.1183/13993003.00955-2020 VO 58 IS 1 A1 Lindsey H.M. te Brake A1 Veronique de Jager A1 Kim Narunsky A1 Naadira Vanker A1 Elin M. Svensson A1 Patrick P.J. Phillips A1 Stephen H. Gillespie A1 Norbert Heinrich A1 Michael Hoelscher A1 Rodney Dawson A1 Andreas H. Diacon A1 Rob E. Aarnoutse A1 Martin J. Boeree YR 2021 UL http://erj.ersjournals.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