Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses

Abstract

The pharmacokinetics and safety of ceftolozane, a novel cephalosporin, and tazobactam, a ␤-lactamase inhibitor, alone and in combination as a 2:1 ratio in single doses of up to 2,000 and 1,000 mg of ceftolozane and tazobactam, respectively, and multiple doses of up to 3,000 and 1,500 mg of ceftolozane and tazobactam, respectively, per day were evaluated in healthy adult subjects. In part 1, groups of six subjects each received single ascending doses of ceftolozane, tazobactam, and ceftolozane-tazobactam in a within-cohort crossover design. In part 2, groups of 5 or 10 subjects each received multiple doses of ceftolozane, tazobactam, or ceftolozane-tazobactam for 10 days. After a single dose of ceftolozane alone, the ranges of mean values for half-life (2.48 to 2.64 h), the total clearance (4.35 to 6.01 liters/h), and the volume of distribution at steady state (11.0 to 14.1 liters) were consistent across dose levels and similar to those observed when ceftolozane was coadministered with tazobactam. Mean values after multiple doses for ceftolozane alone and ceftolozane-tazobactam were similar to those seen following a single dose. The pharmacokinetics of the dosing regimens evaluated were dose proportional and linear. Ceftolozane-tazobactam was well tolerated and systemic adverse events were uncommon. Mild infusion-related adverse events were the most commonly observed following multiple-dose administration. Adverse events were not dose related, and no dose-limiting toxicity was identified.T he emergence of drug resistance in common pathogens has become a major medical issue; increased resistance in Gram-negative pathogens, such as Pseudomonas aeruginosa and extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae, is especially concerning due to the increased morbidity and mortality associated with such infections (5). However, the number of antimicrobial products currently being developed to address these unmet medical needs appears to be limited (1).Ceftolozane-tazobactam, formerly referred to as CXA-201, is a novel oxyimino-aminothiazolyl cephalosporin (ceftolozane) and ␤-lactamase inhibitor (tazobactam) combination being developed for the treatment of serious Gram-negative infections (6,7,8). The addition of tazobactam extends its spectrum of activity to cover ESBL-producing organisms. The pharmacokinetics (PK) and safety of multiple doses of ceftolozane alone has already been established (3) but needs to be investigated for the coadministration of ceftolozane and tazobactam. In the present study, the PK and safety of single and multiple doses of ceftolozane and tazobactam alone and in combination at a 2:1 ratio were investigated in healthy adult subjects. MATERIALS AND METHODSStudy population and study design. Healthy male and female subjects, 18 to 65 years of age, were enrolled in a single-center, prospective, randomized, double blind study of single ascending doses (part 1) and multiple ascending doses (part 2) of intravenous (i.v.) ceftolozane, tazobactam, and ceftolozane-tazobactam. In part 1, t...

Plasma and Epithelial Lining Fluid Pharmacokinetics of Ceftolozane and Tazobactam Alone and in Combination in Mice

“…One possible reason might be that the doses used in our study were low enough not to show any; in the study by Bulik et al, the dosing regimens were adjusted by lowering the dose but giving doses more often to account for drug interactions. In humans, such a drug interaction is not observed (9).…”

“…In addition, it is not clear whether pharmacokinetic interactions exist between cephalosporins and tazobactam. In one earlier, limited study, such a pharmacokinetic interaction was observed between these two compounds (8) in mice, although it was not observed in men (9). Thus, the primary objectives of this study were to evaluate the pharmacokinetic profiling of ceftolozane and tazobactam in the mouse plasma and ELF and to assess potential drug interactions using a neutropenic murine thigh or lung infection model.…”

Ceftolozane/Tazobactam

“…1 Overall, the terminal half-life is approximately 2.5 hours for ceftolozane and 1 hour for tazobactam. [2][3][4] The C max and AUC increased in proportion to dose, while the elimination half-life was independent of dose. 1,3 In patients with normal renal function, the pharmacokinetics of ceftolozane/tazobactam are linear across a large range of doses.…”

“…[2][3][4] The C max and AUC increased in proportion to dose, while the elimination half-life was independent of dose. 1,3 In patients with normal renal function, the pharmacokinetics of ceftolozane/tazobactam are linear across a large range of doses. [2][3][4] Steady-state volume of distribution in healthy adults was 13.5 L for ceftolozane and 18.2 L for tazobactam.…”

“…1,3 In patients with normal renal function, the pharmacokinetics of ceftolozane/tazobactam are linear across a large range of doses. [2][3][4] Steady-state volume of distribution in healthy adults was 13.5 L for ceftolozane and 18.2 L for tazobactam. 1 Moderate renal function impairment led to higher concentrations of ceftolozane and tazobactam and increased AUC by 2.5-fold for ceftolozane and 1.6-fold tazobactam.…”