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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{triangledown}

Navita L. Mallalieu,1* Siân Lennon,2 Mei Liu,1 Christopher Kirkpatrick,2 Richard Robson,3 Eric Luedin,4 and Brian E. Davies1

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 (Cmax) increased with a maximum difference of 44% between the severe and normal groups. In contrast, the corresponding increase in Cmax 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.

* Corresponding author. Mailing address: Department of Clinical Pharmacology, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110. Phone: (973) 235-6072. Fax: (973) 235-8798. E-mail: navita_l.mallalieu{at}roche.com

{triangledown} Published ahead of print on 28 April 2008.

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.



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