Lindsey H M Te Brake1, Veronique de Jager2, Kim Narunsky3, Naadira Vanker2, Elin M Svensson1,4, Patrick P J Phillips5, Stephen H Gillespie6, Norbert Heinrich7,8, Michael Hoelscher7,8, Rodney Dawson3, Andreas H Diacon2, Rob E Aarnoutse1, Martin J Boeree. 1. Dept of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 2. TASK Applied Science, Cape Town, South Africa. 3. UCT Lung Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. 4. Dept of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. 5. UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, CA, USA. 6. School of Medicine, Medical and Biological Sciences, University of St Andrews, St Andrews, UK. 7. Division of Infectious Diseases and Tropical Medicine, Medical Center of the University of Munich, Munich, Germany. 8. German Center for Infection Research (DZIF), Munich, Germany.
Abstract
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.
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.
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