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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 (AUC 0–24 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&lt;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) log 10 CFU·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.

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg−1 rifampicin

Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg⁻¹ rifampicin