A dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosis
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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.
Boeree , M J , Diacon , A H , Dawson , R , Narunsky , K , du Bois , J , Venter , A , Phillips , P P J , Gillespie , S H , Mc Hugh , T D , Hoelscher , M , Heinrich , N , Rehal , S , van Soolingen , D , van Ingen , J , Magis-Escurra , C , Burger , D , Plemper van Balen , G & Aarnoutse , R E 2015 , ' A dose ranging trial to optimize the dose of Rifampin in the treatment of tuberculosis ' American Journal of Respiratory and Critical Care Medicine , vol 191 , no. 9 , pp. 1058-1065 . DOI: 10.1164/rccm.201407-1264OC
American Journal of Respiratory and Critical Care Medicine
© 2015, Publisher / the Author(s). This work is made available online in accordance with the publisher’s policies. This is the author created, accepted version manuscript following peer review and may differ slightly from the final published version. The final published version of this work is available at www.atsjournals.org / https://dx.doi.org/10.1164/rccm.201407-1264OC
The study was funded by the EDCTP (European & Developing Countries Clinical Trials Partnership), NACCAP (Netherlands-African partnership for Capacity development and Clinical interventions Against Poverty-related diseases) and the Bill & Melinda Gates Foundation.
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