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

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 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 cohort (n=15), 13 patients experienced a total of 36 adverse events during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg 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, 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) for 50 mg·kg compared with 40 mg·kg; 571 (range 320-995) 387 (range 201-847) mg·L·h, while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg (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: 14-day EBA -0.427 (95% CI -0.500- -0.355) logCFU·mL·day.

Conclusion: Although associated with an increased bactericidal effect, the 50 mg·kg dose was not well tolerated. Rifampicin at 40 mg·kg was well tolerated and therefore selected for evaluation in a phase IIc treatment-shortening trial.