Increased Bactericidal Activity But Dose-Limiting Tolerability at 50 mg/kg Rifampicin

Abstract

Background: Accumulating data indicate that higher rifampicin doses may be more effective and shorten tuberculosis treatment duration. This study evaluated the safety, tolerability, pharmacokinetics, and 14-day early bactericidal activity (EBA) of increasing doses of rifampicin. Methods: We performed a dose-escalation study in treatment-naive adult smear-positive tuberculosis patients. Patients received, in consecutive cohorts, 40 or 50mg/kg rifampicin once daily in monotherapy (day 1-7), supplemented with standard doses of isoniazid, pyrazinamide and ethambutol between day 8-14. Safety, tolerability, pharmacokinetics, and EBA were assessed. Findings: In the 40mg/kg cohort (n=15), 13 patients experienced adverse events (AEs) during monotherapy (n=36), resulting in one treatment discontinuation in the combination phase. In the 50mg/kg group (n=17), all patients experienced AEs during monotherapy. There were more AEs in total (n=93) compared to 40mg/kg, and eleven patients withdrew or stopped study medication. AEs were mostly mild or moderate (≤grade 3) and tolerability related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. A more than proportional increase in rifampicin exposure with dose was observed, in line with previous cohorts. EBA increased considerably with dose; with the highest seen in the 50mg/kg cohort. Interpretation: Our research concludes a journey that started in the 1960s. Rifampicin up to 40mg/kg was well tolerated. Although associated with an increased bactericidal effect, the tolerability of a 50mg/kg dose was poor. Rifampicin at 40mg/kg appears to be the optimal dose for evaluation in a phase IIB/C treatment shortening trial. Trial Registration: Here we report the results of the final cohorts of the PanACEA HIGHRIF1 trial (clinicaltrials.gov NCT01392911). Funding Statement: This publication was produced by PanACEA, which is part of the European and Developing Countries Clinical Trials Partnership (EDCTP) 1 programme [project code IP.2007.32011.012 (HIGHRIF)] and the EDCTP2 programme supported by the European Union (grant number TRIA2015-1102-PanACEA). Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study protocol was approved by the applicable ethical review boards and by the South African Health Products Regulatory Authority and was conducted according to international and South African Good Clinical Practice guidelines.