Effect of impaired renal function on the pharmacokinetics of tomopenem (RO4908463/CS-023), a novel carbapenem

Department of Clinical Pharmacology, Hoffmann-La Roche, Nutley Inc., NJ; Roche Products Ltd., Welwyn, UK; Christchurch Clinical Studies Trust, Christchurch, New Zealand; and F. Hoffmann-La Roche, Basel, Switzerland

^* To whom correspondence should be addressed. Email: navita_l.mallalieu{at}roche.com.

	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 80, 50-79, 30-49 and <30 mL/min, respectively. The drug was given as a single 1500 mg constant rate intravenous infusion over 60 minutes. 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) AUCs for tomopenem increased with decreasing renal function from 191 ± 35.2 to 1037 ± 238 µg·h/mL. C_max values for tomopenem 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-squared = 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 L/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 metabolite.