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Antimicrobial Agents and Chemotherapy, September 2009, p. 3720-3725, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00106-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects{triangledown}

Ann M. Ginsberg,1 Martino W. Laurenzi,1 Doris J. Rouse,2* Karl D. Whitney,2 and Melvin K. Spigelman1

Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005,1 RTI International, 3040 Cornwallis Road, P.O. Box 12194, Research Triangle Park, North Carolina 277092

Received 25 January 2009/ Returned for modification 26 March 2009/ Accepted 3 June 2009

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 µg/ml for drug-sensitive strains and between 0.03 and 0.53 µg/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 µg/ml (1,500-mg dose) in the single-dose study and 3.8 µg/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.

* Corresponding author. Mailing address: RTI International, 3040 Cornwallis Rd., P.O. Box 12194, Research Triangle Park, NC 27709. Phone: (919) 541-6980. Fax: (919) 541-6621. E-mail: rouse{at}rti.org

{triangledown} Published ahead of print on 15 June 2009.

Antimicrobial Agents and Chemotherapy, September 2009, p. 3720-3725, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00106-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Ginsberg, A. M., Laurenzi, M. W., Rouse, D. J., Whitney, K. D., Spigelman, M. K. (2009). Assessment of the Effects of the Nitroimidazo-Oxazine PA-824 on Renal Function in Healthy Subjects. Antimicrob. Agents Chemother. 53: 3726-3733 [Abstract] [Full Text]  


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