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A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis.
- Source :
-
American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2015 May 01; Vol. 191 (9), pp. 1058-65. - Publication Year :
- 2015
-
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.<br />Objectives: To evaluate the safety and tolerability, the pharmacokinetics, and the extended early bactericidal activity of increasing doses of rifampin.<br />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.<br />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 log10 colony-forming units/ml sputum in the 10, 20, 25, 30, and 35 mg/kg groups, respectively.<br />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. Clinical trial registered with www.clinicaltrials.gov (NCT 01392911).
- Subjects :
- Adolescent
Adult
Antibiotics, Antitubercular pharmacokinetics
Bacterial Load drug effects
Drug Therapy, Combination
Ethambutol administration & dosage
Female
Humans
Isoniazid administration & dosage
Male
Middle Aged
Pyrazinamide administration & dosage
Rifampin pharmacokinetics
Tuberculosis, Pulmonary microbiology
Young Adult
Antibiotics, Antitubercular administration & dosage
Drug Dosage Calculations
Rifampin administration & dosage
Tuberculosis, Pulmonary drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1535-4970
- Volume :
- 191
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- American journal of respiratory and critical care medicine
- Publication Type :
- Academic Journal
- Accession number :
- 25654354
- Full Text :
- https://doi.org/10.1164/rccm.201407-1264OC