A dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosis

Martin J Boeree, Andreas H Diacon, Rodney Dawson, Kim Narunsky, Jeannine du Bois, Amour Venter, Patrick P J Phillips, Stephen H Gillespie, Timothy D Mc Hugh, Michael Hoelscher, Norbert Heinrich, Sunita Rehal, Dick van Soolingen, Jakko van Ingen, Cecile Magis-Escurra, David Burger, Georgette Plemper van Balen, Rob E Aarnoutse, PanACEA Consortium

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251 Citations (Scopus)

Abstract

Rationale: Rifampin at a dose of 10 mg/kg was introduced in 1971 based on pharmacokinetic, toxicity and cost considerations. Available data in mice and humans showed that an increase in dose may shorten the duration of tuberculosis treatment. Objectives: To evaluate the safety and tolerability, the pharmacokinetics and the extended early bactericidal activity of increasing doses of rifampin. Methods: Patients with drug-susceptible tuberculosis were enrolled into a control group of 8 patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20 mg/kg, 25 mg/kg, 30 mg/kg and 35 mg/kg, respectively, for 14 days. In all patients isoniazid, pyrazinamide and ethambutol were added in standard doses for the second 7 days of treatment. Safety, pharmacokinetics of rifampin, and fall in bacterial load were assessed. Measurements and Main Results: Grade 1 and 2 adverse events were equally distributed between the five dose groups; there were 5 grade 3 events of which 1 was a possibly related hepatotoxicity. Areas under the time-concentration curves and peak serum concentrations of rifampin showed a more than proportional increase with dose. The daily fall in bacterial load over 14 days was 0.176, 0.168, 0.167, 0.265, and 0.261 log10CFU/ml sputum in the 10, 20, 25, 30 and 35 mg/kg groups respectively. Conclusions: Two weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a non-linear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups. Clinical trial registration available at www.clinicaltrials.gove, ID NCT01392911.
Original languageEnglish
Pages (from-to)1058-1065
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume191
Issue number9
Early online date5 Feb 2015
DOIs
Publication statusPublished - 1 May 2015

Keywords

  • Tuberculosis
  • Clinical trial
  • Rifampicin
  • Global health

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