title: Phase II dose-ranging trial of the early bactericidal activity of PA-824.
abstract: PA-824 is a novel nitroimidazo-oxazine under evaluation as an antituberculosis agent. A dose-ranging randomized study was conducted to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive adult pulmonary-tuberculosis patients to find the lowest dose giving optimal bactericidal activity (EBA). Fifteen patients per cohort received oral PA-824 in doses of 50 mg, 100 mg, 150 mg, or 200 mg per kg body weight per day for 14 days. Eight subjects received once-daily standard antituberculosis treatment with isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) as a positive control. The primary efficacy endpoint was the mean rate of decline in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log(10) CFU/day/ml sputum (± standard deviation). The mean 14-day EBA of HRZE was consistent with previous studies (0.177 ± 0.042), and that of PA-824 at 50 mg, 100 mg, 150 mg, and 200 mg was 0.063 ± 0.058, 0.091 ± 0.073, 0.078 ± 0.074, and 0.112 ± 0.070, respectively. Although the study was not powered for testing the difference between arms, there was a trend toward significance, indicating a lower EBA at the 50-mg dose. Serum PA-824 levels were approximately dose proportional with respect to the area under the time-concentration curve. All doses were safe and well tolerated with no dose-limiting adverse events or clinically significant QTc changes. A dose of 100 mg to 200 mg PA-824 daily appears to be safe and efficacious and will be further evaluated as a component of novel antituberculosis regimens for drug-sensitive and drug-resistant tuberculosis.
authors.affiliation: Division of Physiology, Department of Medical Biochemistry, Faculty of Health Sciences, Stellenbosch University, 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: Jeannine
authors.initials: J
authors.lastname: du Bois
authors.forename: Kim
authors.initials: K
authors.lastname: Narunsky
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: Ngozi
authors.initials: N
authors.lastname: Erondu
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ginsberg
authors.forename: Piet
authors.initials: P
authors.lastname: Becker
authors.forename: Melvin K
authors.initials: MK
authors.lastname: Spigelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004977:Ethambutol / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011718:Pyrazinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin