Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections

Abstract

Ceftolozane/tazobactam is a novel antipseudomonal cephalosporin and β-lactamase inhibitor in clinical development for treatment of complicated urinary tract (cUTI) and intra-abdominal (cIAI) infections and nosocomial pneumonia. The population pharmacokinetics of ceftolozane/tazobactam were characterized in healthy volunteers, subjects with varying degrees of renal function, and patients with cIAI or cUTI. Serum concentration data from 376 adults who received ceftolozane/tazobactam in doses ranging from 500 to 3000 mg were analyzed to identify factors contributing to the pharmacokinetic variability. Ceftolozane/tazobactam pharmacokinetics were well described by a linear two-compartment model with first-order elimination and moderate between-subject variability in both clearance and volume of distribution (Vc). For both ceftolozane and tazobactam, clearance was highly correlated with renal function with creatinine clearance influencing exposure, and infection influencing Vc. Body weight was an additional covariate affecting the Vc of ceftolozane. Other covariates tested, such as age, body weight, sex, ethnicity, and presence of infection, had no clinically relevant effects on exposure. The final pharmacokinetic models adequately described the plasma concentrations of ceftolozane and tazobactam and form the basis for further modeling and simulation including evaluation of probability of target attainment in a diverse population with varying demographics, degrees of renal function, and infection status.

Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation

“…In contrast with Chandorkar and colleagues, we were not able to identify any significant relationship between actual body weight and volume of the central compartment (V c ) for ceftolozane with linear or allometric scaling (22). Other body weight descriptors (lean body weight, BMI, and fat free mass) were also not significantly associated with the volume of the central compartment in our CF population.…”

“…These findings suggest that there is an ϳ10% change in ceftolozane clearance for every 20% increase or decrease in CL CR . Similarly, a population pharmacokinetic study including healthy volunteers and non-CF patients observed clearance to change by ϳ15% for every 20% change in CL CR (22). We did not identify any direct relationships with body size descriptors and ceftolozane clearance, which is also reflective of the findings by Chandorkar and colleagues (22).…”

“…Similarly, a population pharmacokinetic study including healthy volunteers and non-CF patients observed clearance to change by ϳ15% for every 20% change in CL CR (22). We did not identify any direct relationships with body size descriptors and ceftolozane clearance, which is also reflective of the findings by Chandorkar and colleagues (22). Importantly, mean clearance estimates for our patients and adults without CF with normal kidney function were similar (CF CL, 4.76 liters/h; non-CF CL, 5.11 liters/h) (22).…”

“…This antibiotic retains activity against P. aeruginosa isolates not susceptible to other commonly used antipseudomonal agents and has demonstrated excellent penetration into the epithelial lining fluid of healthy volunteers (8,20,21). The pharmacokinetics of ceftolozane-tazobactam have been studied in healthy volunteers, patients with renal dysfunction, and patients with active infections (5,22). However, to our knowledge, this is the first pharmacokinetic study of ceftolozane and tazobactam in adults with CF during an acute pulmonary exacerbation.…”

Ceftolozane/Tazobactam

“…1,2 The in vitro minimum inhibitory concentration (MIC) varies by organisms and method (see Table 1). 1 Ceftolozane/tazobactam has activity against gramnegative bacilli, including beta-lactamase-producing bacteria P. aeruginosa; various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates; strains that are multidrug-resistant; most extended-spectrum betalactamase producers; and some anaerobic species.…”