title: Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.
abstract: PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (+/-standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/-0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/-0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.
authors.affiliation: Department of Medical Biochemistry, Faculty of Health Sciences, University of Stellenbosch, Cape Town, South Africa. ahd@sun.ac.za
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
authors.forename: Rodney
authors.initials: R
authors.lastname: Dawson
authors.forename: Madeleine
authors.initials: M
authors.lastname: Hanekom
authors.forename: Kim
authors.initials: K
authors.lastname: Narunsky
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Maritz
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.forename: Peter R
authors.initials: PR
authors.lastname: Donald
authors.forename: Christo
authors.initials: C
authors.lastname: van Niekerk
authors.forename: Karl
authors.initials: K
authors.lastname: Whitney
authors.forename: Doris J
authors.initials: DJ
authors.lastname: Rouse
authors.forename: Martino W
authors.initials: MW
authors.lastname: Laurenzi
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ginsberg
authors.forename: Melvin K
authors.initials: MK
authors.lastname: Spigelman
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003470:Culture Media; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D009593:Nitroimidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013183:Sputum / Q000382:microbiology; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D003470:Culture Media; D009593:Nitroimidazoles; C410767:pretomanid