Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients

A Prospective, Multicenter, Open-Label Study to Assess Population Pharmacokinetics and Safety of Intravenous Ceftolozane/Tazobactam in Adult Cystic Fibrosis Patients Admitted With Acute Pulmonary Exacerbation

There is established evidence that adult patients with Cystic Fibrosis (CF) may have altered antibiotic pharmacokinetics compared with non-CF patients. Ceftolozane/Tazobactam is a newly approved broad spectrum intravenous antibiotic, which has potent in vitro activity against multidrug resistant Pseudomonas aeruginosa, the most common pathogen implicated in CF pulmonary exacerbations. This study will determine the pharmacokinetics and tolerability of ceftolozane/tazobactam in 20 adult CF patients admitted for a pulmonary exacerbation at one of 4 participating hospitals in the US. Patients will remain on standard of care IV antibiotics and receive 4-6 doses of ceftolozane/tazobactam 3 grams every 8 hours. Blood will be sampled after the final dose to determine concentrations and pharmacokinetics of ceftolozane and tazobactam. Safety and tolerability will be assessed throughout the 3 day study.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis; Cystic Fibrosis Pulmonary Exacerbation; Pseudomonas Aeruginosa Infection
• Intervention / Treatment: Drug: Ceftolozane/Tazobactam

Detailed Description

Participants will receive 4-6 doses of ceftolozane/tazobactam 3 grams every 8 hours, in addition to standard intravenous antibiotic therapy selected by the site. Just prior and then after the final dose, a total of six blood samples will be collected to measure ceftolozane and tazobactam concentrations. Data will be fit to a population pharmacokinetic model. The final model will be utilized in a Monte Carlo simulation to determine the probability of several different dosing regimens retaining concentrations above the minimum inhibitory concentration (MIC) for at least 39% of the dosing interval. These data will be utilized to determine an optimized dosing regimen for adults with CF.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children at Indiana University Health
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 years or older
2. Documented diagnosis of CF
3. Acute pulmonary exacerbation as the primary reason for admission to the hospital with requirement to receive systemic antibiotic treatment
4. If female, subjects must be non-pregnant and non-lactating. Females can be either not of a child-bearing potential or if of a child-bearing potential, on acceptable modes of birth control such as abstinence from sexual intercourse, oral/parenteral contraceptives, or barrier method

Exclusion Criteria:

1. History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibiotic (a history of mild rash to a cephalosporin followed by uneventful re-exposure is not a contraindication)
2. Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam or probenecid
3. History of lung transplant
4. Moderate to severe renal dysfunction defined as a creatinine clearance < 50 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) or requirement for continuous renal replacement therapy or hemodialysis
5. A hemoglobin less than 8 gm/dl at baseline
6. Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator)
7. Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data
8. Planned or prior participation in any other interventional drug study within 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftolozane/Tazobactam; Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses	Drug: Ceftolozane/Tazobactam; 1 hour intravenous infusion; Other Names: Zerbaxa; CXA-101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ceftolozane Clearance	This outcome determines the clearance of ceftolozane over the 8 hour dosing interval.	0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
Ceftolozane Volume of Distribution (Central Compartment)	This outcome determines the volume of distribution of ceftolozane over the 8 hour dosing interval.	0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
Tazobactam Clearance	This outcome determines the clearance of tazobactam over the 8 hour dosing interval.	0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
Tazobactam Volume of Distribution (Central Compartment)	This outcome determines the volume of distribution of tazobactam over the 8 hour dosing interval.	0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ceftolozane Probability of Target Attainment at 8 mcg/ml	This simulated outcome indicates the likelihood that ceftolozane will retain drug concentrations above the MIC for >/= 60% of the dosing interval at an MIC of 8 mcg/ml when administered as a 3g (2g ceftolozane/1g tazobactam) every 8 hour dose infused over 1 hour. This analysis is conducted via a Monte Carlo simulation using the population pharmacokinetic parameter estimates and dispersion from the 20 participants who contributed pharmacokinetic data to the study.	24 hours

Collaborators and Investigators

• Sponsor: Joseph L. Kuti, PharmD
• Collaborators: Cubist Pharmaceuticals LLC; Indiana University Health; University of North Carolina; St. Christopher's Hospital for Children
• Investigators: Principal Investigator: Joseph L Kuti, PharmD, Hartford Hospital

Publications and helpful links

General Publications

• Monogue ML, Pettit RS, Muhlebach M, Cies JJ, Nicolau DP, Kuti JL. Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation. Antimicrob Agents Chemother. 2016 Oct 21;60(11):6578-6584. doi: 10.1128/AAC.01566-16. Print 2016 Nov.

Study record dates

Study Major Dates

• Study Start: September 1, 2015
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): October 1, 2016

Study Registration Dates

• First Submitted: April 13, 2015
• First Submitted That Met QC Criteria: April 17, 2015
• First Posted (Estimate): April 20, 2015

Study Record Updates

• Last Update Posted (Actual): August 4, 2020
• Last Update Submitted That Met QC Criteria: July 27, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Pancreatic Diseases; Fibrosis; Pulmonary Fibrosis; Cystic Fibrosis; Pseudomonas Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Anti-Infective Agents, Urinary; Renal Agents; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination
• Other Study ID Numbers: HHC-2015-0107