title: Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects.
abstract: PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 microg/ml for drug-sensitive strains and between 0.03 and 0.53 microg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 microg/ml (1,500-mg dose) in the single-dose study and 3.8 microg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.
authors.affiliation: Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, USA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Ginsberg
authors.forename: Martino W
authors.initials: MW
authors.lastname: Laurenzi
authors.forename: Doris J
authors.initials: DJ
authors.lastname: Rouse
authors.forename: Karl D
authors.initials: KD
authors.lastname: Whitney
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*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid