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Antimicrobial Agents and Chemotherapy, September 2009, p. 3726-3733, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00112-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Assessment of the Effects of the Nitroimidazo-Oxazine PA-824 on Renal Function in Healthy Subjects{triangledown}

Ann M. Ginsberg,1 Martino W. Laurenzi,1 Doris J. Rouse,2* Karl D. Whitney,2 and Mel 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 26 January 2009/ Returned for modification 26 March 2009/ Accepted 3 June 2009

The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.

* 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. 3726-3733, Vol. 53, No. 9
0066-4804/09/$08.00+0     doi:10.1128/AAC.00112-09
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). Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects. Antimicrob. Agents Chemother. 53: 3720-3725 [Abstract] [Full Text]  


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