title: A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  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).
authors: 1 Department of Lung Diseases.
authors: Martin J
authors: MJ
authors: Boeree
authors: Andreas H
authors: AH
authors: Diacon
authors: Rodney
authors: R
authors: Dawson
authors: Kim
authors: K
authors: Narunsky
authors: Jeannine
authors: J
authors: du Bois
authors: Amour
authors: A
authors: Venter
authors: Patrick P J
authors: PP
authors: Phillips
authors: Stephen H
authors: SH
authors: Gillespie
authors: Timothy D
authors: TD
authors: McHugh
authors: Michael
authors: M
authors: Hoelscher
authors: Norbert
authors: N
authors: Heinrich
authors: Sunita
authors: S
authors: Rehal
authors: Dick
authors: D
authors: van Soolingen
authors: Jakko
authors: J
authors: van Ingen
authors: Cecile
authors: C
authors: Magis-Escurra
authors: David
authors: D
authors: Burger
authors: Georgette
authors: G
authors: Plemper van Balen
authors: Rob E
authors: RE
authors: Aarnoutse
mesh_terms: D000293:Adolescent; D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000493:pharmacokinetics; D058491:Bacterial Load / Q000187:drug effects; D054796:Drug Dosage Calculations; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D011718:Pyrazinamide / Q000008:administration & dosage; D012293:Rifampin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000904:Antibiotics, Antitubercular; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin
keywords: antitubercular agents; clinical trial; dose–response relationship; drug therapy; pharmacokinetics