title: Effect of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem.
abstract: 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 > or =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 microg.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 (R(2) = 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.
authors.affiliation: Department of Clinical Pharmacology, Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, USA. navita_l.mallalieu@roche.com
authors.forename: Navita L
authors.initials: NL
authors.lastname: Mallalieu
authors.forename: Siân
authors.initials: S
authors.lastname: Lennon
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Christopher
authors.initials: C
authors.lastname: Kirkpatrick
authors.forename: Richard
authors.initials: R
authors.lastname: Robson
authors.forename: Eric
authors.initials: E
authors.lastname: Luedin
authors.forename: Brian E
authors.initials: BE
authors.lastname: Davies
mesh_terms: D000328:Adult; D000368:Aged; D001424:Bacterial Infections / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D015780:Carbapenems / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D003404:Creatinine / Q000378:metabolism; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D051437:Renal Insufficiency / Q000150:complications / Q000378:metabolism*
chemical_list: D015780:Carbapenems; C492232:tomopenem; D003404:Creatinine