Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 191, Issue 9, Pages 1058-1065Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.201407-1264OC
Keywords
antitubercular agents; dose-response relationship; pharmacokinetics; drug therapy; clinical trial
Categories
Funding
- European and Developing Countries Clinical Trials Partnership
- Netherlands-African Partnership for Capacity Development and Clinical Interventions Against Poverty-related Diseases
- Bill and Melinda Gates Foundation
- Medical Research Council [MC_UU_12023/27, MC_U122888469] Funding Source: researchfish
- MRC [MC_UU_12023/27, MC_U122888469] Funding Source: UKRI
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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 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 Results: Grade 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 log(10) colony-forming units/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 nonlinear increase in exposure to rifampin without an apparent ceiling effect and a greater estimated fall in bacterial load in the higher dosing groups.
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