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

Abstract

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.PA-824 is a new chemical entity member of the class of compounds known as nitroimidazo-oxazines. PA-824 possesses significant antitubercular activity and a unique mechanism of action. Nonclinical studies of PA-824 highlighted important properties that may result in significant improvements in tuberculosis (TB) treatment. PA-824 demonstrated in vitro activity against both drug-sensitive and multidrug-resistant strains of TB and in vivo activity in a mouse model of TB (9, 11). In initial clinical studies to assess pharmacokinetics, safety, and tolerability in healthy volunteers, consistent, dose-dependent, and reversible elevations in serum creatinine (SC) were observed (4). Any one of several mechanisms could account for an increase in SC, including increased protein catabolism, reduced glomerular filtration rate (GFR), change in effective renal plasma flow (ERPF), and the inhibition of creatinine secretion by the renal proximal tubules. In subjects with normal renal function, the tubular secretion of creatinine can represent up to 40% of the total renal clearance of creatinine (10). A number of drugs, including pyrimethamine (1, 12), cimetidine (5, 8), and trimethoprim (7, 14), increase SC as a result of the clinically benign process of reducing tubular creatinine secretion, usually through competitive inhibition rather than through a pathological process that results in reduced GFR and/or effects on...

A New Hope in TB Treatment: The Development of the Newest Drugs

“…Moxifloxacin could be of use in the treatment of latent TB (Hu et al, 2008). The combination of 3 months of once-weekly moxifloxacin and rifapentine was as effective as 6 months of isoniazid monotherapy in a mouse model for latent TB (Ginsberg et al, 2009b). A single dose moxifloxacin of up to 800mg was tolerated well but little is known about the long-term tolerability in TB patients.…”

“…The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrugresistant M. tuberculosis with no influence of serum concentration by coadministration of RIF, INH, PZA in various combinations Ginsberg et al, 2009a), support investigation of this novel compound for the treatment of tuberculosis. Since multiple doses of 1000mg were associated with a moderate, reversible increase in creatinine, Ginsberg et al made a further assessment (Ginsberg et al, 2009b) of the effects of PA-824 on renal function in healthy subjects. The results suggests that PA-824 causes creatinine level to rise by inhibiting renal tubular creatinine secretion and such an effect is considered clinically benign since it has been described for several marketed drugs.…”

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“…In humans, PA-824 has been well tolerated with constant pharmacodynamic parameters when given once daily, with the maximum serum drug level reached about 4-5 h following oral administration [59,67,68].…”

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“…There were initial concerns about the effect of PA-824 on renal function in man. Although it reduces creatinine excretion in a reversible fashion, it does not reduce the glomerular filtration rate and it does not significantly affect any other aspect of renal physiology [Ginsburg et al 2009]. Similar to PA-824, OPC-67683 is a prodrug and requires in vivo metabolic activation [Mukherjee and Boshoff, 2011].…”