• Martin J Boeree, Andreas H Diacon, Rodney Dawson, Kim Narunsky, Jeannine du Bois, Amour Venter, Patrick P J Phillips, Stephen H Gillespie, Timothy D McHugh, Michael Hoelscher, Norbert Heinrich, Sunita Rehal, Dick van Soolingen, Jakko van Ingen, Cecile Magis-Escurra, David Burger, Georgette Plemper van Balen, Rob E Aarnoutse, and PanACEA Consortium.
• 1 Department of Lung Diseases.
• Am. J. Respir. Crit. Care Med. 2015 May 1; 191 (9): 1058-65.

RationaleRifampin 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.ObjectivesTo evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin.MethodsPatients with drug-susceptible tuberculosis were enrolled into a control group of eight patients receiving the standard dose of 10 mg/kg rifampin, followed by consecutive experimental groups with 15 patients each receiving rifampin 20, 25, 30, 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 ResultsGrade 1 and 2 adverse events were equally distributed between the five dose groups; there were five grade 3 events of which one 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 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively.ConclusionsTwo weeks of rifampin up to 35 mg/kg was safe and well tolerated. There was a nonlinear 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 registered with www.clinicaltrials.gov (NCT 01392911).

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