Impact of renal function on the pharmacokinetics and safety of ceftolozane-tazobactam

Abstract

Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a β-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-∞) for ceftolozane and tazobactam increased 1.4- and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC0-∞ increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-∞ for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-∞ before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups.

FIG 1

Profiles of median (range) ceftolozane (A) and tazobactam (B) concentrations in plasma versus time following a single-dose administration of intravenous ceftolozane-tazobactam (semilog plots). C/T, ceftolozane-tazobactam; RI, renal impairment.

FIG 2

Regression plots of ceftolozane (A) and tazobactam (B) plasma clearance versus CL_CR following a single-dose intravenous administration of ceftolozane-tazobactam. C/T, ceftolozane-tazobactam; RI, renal impairment.

FIG 3

Profiles of median (range) ceftolozane and tazobactam concentrations in plasma versus time following the intravenous administration of ceftolozane-tazobactam (500/250 mg) in subjects with ESRD on day 1 (post-HD) (A) and day 4 (on HD) (B) (semilog plots).