title: Defining the optimal dose of rifapentine for pulmonary tuberculosis: Exposure-response relations from two phase II clinical trials.
abstract: Rifapentine is a highly active antituberculosis antibiotic with treatment-shortening potential; however, exposure-response relations and the dose needed for maximal bactericidal activity have not been established. We used pharmacokinetic/pharmacodynamic data from 657 adults with pulmonary tuberculosis participating in treatment trials to compare rifapentine (n = 405) with rifampin (n = 252) as part of intensive-phase therapy. Population pharmacokinetic/pharmacodynamic analyses were performed with nonlinear mixed-effects modeling. Time to stable culture conversion of sputum to negative was determined in cultures obtained over 4 months of therapy. Rifapentine exposures were lower in participants who were coinfected with human immunodeficiency virus, black, male, or fasting when taking drug. Rifapentine exposure, large lung cavity size, and geographic region were independently associated with time to culture conversion in liquid media. Maximal treatment efficacy is likely achieved with rifapentine at 1,200 mg daily. Patients with large lung cavities appear less responsive to treatment, even at high rifapentine doses.
authors.affiliation: University of California San Francisco School of Pharmacy, San Francisco, California, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Savic
authors.affiliation: Veterans Administration Medical Center, San Antonio, Texas, USA.|University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: W R
authors.initials: WR
authors.lastname: MacKenzie
authors.affiliation: University of Texas Health Science Center, San Antonio, Texas, USA.
authors.forename: M
authors.initials: M
authors.lastname: Engle
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Whitworth
authors.affiliation: Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, USA.|Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: J L
authors.initials: JL
authors.lastname: Johnson
authors.affiliation: Uganda-Case Western Reserve University Research Collaboration, Kampala, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Nsubuga
authors.affiliation: University of California San Francisco School of Medicine, San Francisco, California, USA.|National Tuberculosis Program, Hanoi, Vietnam.
authors.forename: P
authors.initials: P
authors.lastname: Nahid
authors.affiliation: National Tuberculosis Program, Hanoi, Vietnam.
authors.forename: N V
authors.initials: NV
authors.lastname: Nguyen
authors.affiliation: College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Dooley
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Dorman
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D012293:Rifampin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000453:epidemiology / Q000378:metabolism*
chemical_list: D000904:Antibiotics, Antitubercular; D012293:Rifampin; C018421:rifapentine