Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg(-1) rifampicin
SourceEuropean Respiratory Journal, 58, 1, (2021)
Article / Letter to the editor
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European Respiratory Journal
SubjectRadboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences
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<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.
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