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Antimicrobial Agents and Chemotherapy, July 2008, p. 2360-2366, Vol. 52, No. 7
0066-4804/08/$08.00+0     doi:10.1128/AAC.01249-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Effect of Impaired Renal Function on the Pharmacokinetics of Tomopenem (RO4908463/CS-023), a Novel Carbapenem

Department of Clinical Pharmacology, Hoffmann-La Roche, Nutley, New Jersey,¹ Roche Products Ltd., Welwyn, United Kingdom,² Christchurch Clinical Studies Trust, Christchurch, New Zealand,³ F. Hoffmann-La Roche, Basel, Switzerland⁴

Received 24 September 2007/ Returned for modification 27 December 2007/ Accepted 16 April 2008

The objective of this study was to assess the impact of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem antibiotic, and its major metabolite in humans. Thirty-two subjects were enrolled in an open-label, two-center study. Subjects were evenly assigned to one of four groups, based on creatinine clearance ranges of 80, 50 to 79, 30 to 49, and <30 ml/min. The drug was given as a single 1,500-mg constant-rate intravenous infusion over 60 min. There were no safety concerns with increasing renal dysfunction. Renal impairment had a significant impact on exposure of both tomopenem and its metabolite. Mean (± standard deviation) areas under the curve for tomopenem increased with decreasing renal function, from 191 ± 35.2 to 1,037 ± 238 µg·h/ml. The maximum concentration of drug in plasma (C_max) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in C_max of the metabolite was much higher, at 174%. Total body clearance was linearly correlated with creatinine clearance (R² = 0.97; P < 0.0001). Renal clearance for tomopenem decreased with increasing severity of disease, with mean values decreasing from 4.63 ± 0.89 to 0.59 ± 0.19 liters/h. The results of this study indicated a strong correlation between the creatinine clearance and total clearance of tomopenem. While renal impairment appeared to have a significant effect on the pharmacokinetics of tomopenem, an even greater effect was seen on the elimination of the inactive metabolite.

Published ahead of print on 28 April 2008.