Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg−1 rifampicin
- 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 and
- Martin J. Boeree9
- on behalf of the PanACEA Consortium
- 1Department of Pharmacy, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
- 2TASK Applied Science, Cape Town, South Africa
- 3University of Cape Town Lung institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
- 4Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
- 5UCSF Center for Tuberculosis, University of California San Francisco, San Francisco, United States
- 6School of Medicine, University of St Andrews, St Andrews, United Kingdom
- 7Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany
- 8German Center for Infection Research (DZIF), Munich, Germany
- 9Department of Lung Diseases, Radboud Institute for Health Sciences, Radboud university medical center, Nijmegen, The Netherlands
- Dr Lindsey te Brake, Radboud university medical center, Department of Pharmacy, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. E-mail: lindsey.tebrake{at}radboudumc.nl
Abstract
Accumulating data have indicated that higher rifampicin doses are more effective and shorten tuberculosis 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 tuberculosis. 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 day 8–14. In the 40 mg·kg−1 cohort (n=15), 13 patients experienced a total of 36 adverse events (AEs) during monotherapy, resulting in one treatment discontinuation. In the 50 mg·kg−1 group (n=17), all patients experienced AEs during monotherapy, 93 in total; 11 patients withdrew or stopped study medication. AEs were mostly mild/moderate and tolerability- rather than safety-related, i.e. gastrointestinal disorders, pruritis, hyperbilirubinemia and jaundice. There was a more than proportional increase in the rifampicin geometric mean AUC0–24h for 50 mg·kg−1 compared to 40 mg·kg; 571 mg·L*h−1 (range 320–995) versus 387 mg·L*h−1 (201–847), while peak exposures saw proportional increases. Protein-unbound exposure after 50 mg·kg−1 (11%, 8–17%) was comparable with lower rifampicin doses. Rifampicin exposures and bilirubin concentrations were correlated (day-3 Spearman's rho 0.670, p<0.001). EBA increased considerably with dose, with the highest seen after 50 mg·kg−1; 14-day EBA −0.427 logCFU·mL−1·day−1 (95%CI −0.500, −0.355). In 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.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. te Brake has nothing to disclose.
Conflict of interest: Dr. de Jager has nothing to disclose.
Conflict of interest: Dr. Narunsky has nothing to disclose.
Conflict of interest: Dr. Vanker has nothing to disclose.
Conflict of interest: Dr. Svensson has nothing to disclose.
Conflict of interest: Dr. Phillips reports grants from Ludwig Maximilian University of Munich, during the conduct of the study.
Conflict of interest: Dr. Gillespie reports grants from EDCTP, grants from TB Alliance, outside the submitted work.
Conflict of interest: Dr. Heinrich reports grants from EDCTP, grants from German Ministry for Education and Research, during the conduct of the study; other from AstraZeneca, outside the submitted work.
Conflict of interest: Dr. Hoelscher has nothing to disclose.
Conflict of interest: Dr. Dawson has nothing to disclose.
Conflict of interest: Dr. Diacon has nothing to disclose.
Conflict of interest: Dr. Aarnoutse has nothing to disclose.
Conflict of interest: Dr. Boeree has nothing to disclose.
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- Received April 10, 2020.
- Accepted December 7, 2020.
- Copyright ©ERS 2021