title: 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.
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: Mel K
authors.initials: MK
authors.lastname: Spigelman
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000378:metabolism; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009593:Nitroimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D017596:Renal Plasma Flow, Effective / Q000187:drug effects; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid; D003404:Creatinine