title: Daily rifapentine for treatment of pulmonary tuberculosis. A randomized, dose-ranging trial.
abstract: BACKGROUND
  Rifapentine has potent activity in mouse models of tuberculosis chemotherapy but its optimal dose and exposure in humans are unknown.
  
  
  OBJECTIVE
  We conducted a randomized, partially blinded dose-ranging study to determine tolerability, safety, and antimicrobial activity of daily rifapentine for pulmonary tuberculosis treatment.
  
  
  METHODS
  Adults with sputum smear-positive pulmonary tuberculosis were assigned rifapentine 10, 15, or 20 mg/kg or rifampin 10 mg/kg daily for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. The primary tolerability end point was treatment discontinuation. The primary efficacy end point was negative sputum cultures at completion of intensive phase.
  
  
  RESULTS
  A total of 334 participants were enrolled. At completion of intensive phase, cultures on solid media were negative in 81.3% of participants in the rifampin group versus 92.5% (P = 0.097), 89.4% (P = 0.29), and 94.7% (P = 0.049) in the rifapentine 10, 15, and 20 mg/kg groups. Liquid cultures were negative in 56.3% (rifampin group) versus 74.6% (P = 0.042), 69.7% (P = 0.16), and 82.5% (P = 0.004), respectively. Compared with the rifampin group, the proportion negative at the end of intensive phase was higher among rifapentine recipients who had high rifapentine areas under the concentration-time curve. Percentages of participants discontinuing assigned treatment for reasons other than microbiologic ineligibility were similar across groups (rifampin, 8.2%; rifapentine 10, 15, or 20 mg/kg, 3.4, 2.5, and 7.4%, respectively).
  
  
  CONCLUSIONS
  Daily rifapentine was well-tolerated and safe. High rifapentine exposures were associated with high levels of sputum sterilization at completion of intensive phase. Further studies are warranted to determine if regimens that deliver high rifapentine exposures can shorten treatment duration to less than 6 months. Clinical trial registered with www.clinicaltrials.gov (NCT 00694629).
authors.affiliation: 1 Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Dorman
authors.forename: Radojka M
authors.initials: RM
authors.lastname: Savic
authors.forename: Stefan
authors.initials: S
authors.lastname: Goldberg
authors.forename: Jason E
authors.initials: JE
authors.lastname: Stout
authors.forename: Neil
authors.initials: N
authors.lastname: Schluger
authors.forename: Grace
authors.initials: G
authors.lastname: Muzanyi
authors.forename: John L
authors.initials: JL
authors.lastname: Johnson
authors.forename: Payam
authors.initials: P
authors.lastname: Nahid
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hecker
authors.forename: Charles M
authors.initials: CM
authors.lastname: Heilig
authors.forename: Lorna
authors.initials: L
authors.lastname: Bozeman
authors.forename: Pei-Jean I
authors.initials: PJ
authors.lastname: Feng
authors.forename: Ruth N
authors.initials: RN
authors.lastname: Moro
authors.forename: William
authors.initials: W
authors.lastname: MacKenzie
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Dooley
authors.forename: Eric L
authors.initials: EL
authors.lastname: Nuermberger
authors.forename: Andrew
authors.initials: A
authors.lastname: Vernon
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
mesh_terms: D000293:Adolescent; D000328:Adult; D000349:Africa; D000368:Aged; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage*; D000995:Antitubercular Agents / Q000008:administration & dosage; D001208:Asia; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009656:North America; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D016037:Single-Blind Method; D013020:South America; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D012293:Rifampin; C018421:rifapentine
keywords: mycobacterium; rifamycins; rifapentine; therapeutics; tuberculosis