Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam

Abstract

Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a ␤-lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, openlabel 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 (AUC 0-ؕ ) for ceftolozane and tazobactam increased 1.4-and 1.2-fold, respectively. In subjects with moderate renal impairment, the AUC 0-ؕ increased 2.5-and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC 0-ؕ 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 AUC 0-ؕ 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. C eftolozane-tazobactam is a novel antibacterial with activity against Pseudomonas aeruginosa, including drug-resistant strains, and other common Gram-negative pathogens, including most extended-spectrum ␤-lactamase (ESBL)-producing Enterobacteriaceae (1, 2). Ceftolozane exerts its bactericidal activity by inhibiting essential penicillin-binding proteins, resulting in inhibition of cell wall synthesis and subsequent cell death (Cubist Pharmaceuticals, data on file, 2009). Tazobactam, an inhibitor of most class A ␤-lactamases and some class C ␤-lactamases, protects ceftolozane from hydrolysis and broadens its coverage to include most ESBL-producing members of the family Enterobacteriaceae (Cubist Pharmaceuticals, data on file, 2006, 2013).The pharmacokinetics (PK) of ceftolozane-tazobactam in patients with normal renal function are linear across a wide range of doses (up to 3,000 mg/1,500 mg as a single dose). The terminal elimination half-life (t 1/2 ) is approximately 2.5 h for ceftolozane and 1 h for tazobactam. Both compounds exhibit low protein binding (approximately 20% for ceftolozane and 30% for tazobactam) and are...

Ceftolozane-Tazobactam Pharmacokinetics in a Critically Ill Patient on Continuous Venovenous Hemofiltration

“…The pharmacokinetic and safety profiles of this antibiotic have been established in healthy adults and subjects with various degrees of renal function (1,2). However, there are currently no data guiding its use when administered as an extended infusion in critically ill patients receiving continuous venovenous hemofiltration (CVVH).…”

New antibiotic development: barriers and opportunities

“…10,11 Therefore, subjects with a creatinine clearance equal or lower than 50 mL/min or receiving hemodialysis, require a lower daily dose of ceftolozane/tazobactam and, on hemodialysis days, an administration of the drug after completion of dialysis. 12 In a US multicenter, a surveillance study that included multidrug-resistant P. aeruginosa and Enterobacteriaceae spp., ceftolozane/tazobactam remained active in 79% and 44% of the isolates, respectively. 13 This drug, as well as other cephalosporins, has limited activity against anaerobes, both Gram-negative and positive, hence, when a specific anaerobic coverage is required, an additional agent is recommended.…”

Ceftolozane/Tazobactam

“…For patients with severe renal impairment, the average AUC increased for ceftolozane and tazobactam by 4.5-and 3.8-fold, respectively. 4 The drug plasma concentration is lower after a 3-to 4-hour hemodialysis session, with almost 90% of the initial drug concentration removed from the plasma. 4 Protein binding is low for both compounds (approximately 20% for ceftolozane and 30% for tazobactam) and both are mostly excreted in the urine.…”

“…4 The drug plasma concentration is lower after a 3-to 4-hour hemodialysis session, with almost 90% of the initial drug concentration removed from the plasma. 4 Protein binding is low for both compounds (approximately 20% for ceftolozane and 30% for tazobactam) and both are mostly excreted in the urine. Ceftolozane is excreted as unchanged drug, which suggests minimal metabolism; 80% of tazobactam is excreted unchanged and the other 20% is hydrolyzed to form an inactive tazobactam metabolite M1.…”

“…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.…”