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Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections.
J Clin Pharmacol. 2015 Feb; 55(2):230-9.JC

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.

Authors+Show Affiliations

Cubist Pharmaceuticals, Lexington, MA, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase II
Controlled Clinical Trial
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25196976

Citation

Chandorkar, Gurudatt, et al. "Population Pharmacokinetics of Ceftolozane/tazobactam in Healthy Volunteers, Subjects With Varying Degrees of Renal Function and Patients With Bacterial Infections." Journal of Clinical Pharmacology, vol. 55, no. 2, 2015, pp. 230-9.
Chandorkar G, Xiao A, Mouksassi MS, et al. Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections. J Clin Pharmacol. 2015;55(2):230-9.
Chandorkar, G., Xiao, A., Mouksassi, M. S., Hershberger, E., & Krishna, G. (2015). Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections. Journal of Clinical Pharmacology, 55(2), 230-9. https://doi.org/10.1002/jcph.395
Chandorkar G, et al. Population Pharmacokinetics of Ceftolozane/tazobactam in Healthy Volunteers, Subjects With Varying Degrees of Renal Function and Patients With Bacterial Infections. J Clin Pharmacol. 2015;55(2):230-9. PubMed PMID: 25196976.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections. AU - Chandorkar,Gurudatt, AU - Xiao,Alan, AU - Mouksassi,Mohamad-Samer, AU - Hershberger,Ellie, AU - Krishna,Gopal, Y1 - 2014/11/14/ PY - 2014/05/20/received PY - 2014/09/03/accepted PY - 2014/9/9/entrez PY - 2014/9/10/pubmed PY - 2015/10/13/medline KW - ceftolozane/tazobactam KW - complicated intra-abdominal infections KW - complicated urinary tract infections KW - population pharmacokinetics KW - β-lactam antibacterials SP - 230 EP - 9 JF - Journal of clinical pharmacology JO - J Clin Pharmacol VL - 55 IS - 2 N2 - 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. SN - 1552-4604 UR - https://www.unboundmedicine.com/medline/citation/25196976/Population_pharmacokinetics_of_ceftolozane/tazobactam_in_healthy_volunteers_subjects_with_varying_degrees_of_renal_function_and_patients_with_bacterial_infections_ L2 - https://doi.org/10.1002/jcph.395 DB - PRIME DP - Unbound Medicine ER -