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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02421120
Recruitment Status : Completed
First Posted : April 20, 2015
Results First Posted : April 13, 2017
Last Update Posted : March 19, 2018
Sponsor:
Collaborators:
Cubist Pharmaceuticals LLC
Indiana University Health
University of North Carolina
St. Christopher's Hospital for Children
Information provided by (Responsible Party):
Joseph Kuti, Hartford Hospital

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Cystic Fibrosis Pulmonary Exacerbation Pseudomonas Aeruginosa Infection Drug: Ceftolozane/Tazobactam Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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
Study Start Date : September 2015
Actual Primary Completion Date : March 2016
Actual Study Completion Date : October 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis
Drug Information available for: Tazobactam

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




Primary Outcome Measures :
  1. Ceftolozane Clearance [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the clearance of ceftolozane over the 8 hour dosing interval.

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

  3. Tazobactam Clearance [ Time Frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose ]
    This outcome determines the clearance of tazobactam over the 8 hour dosing interval.

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


Secondary Outcome Measures :
  1. Ceftolozane Probability of Target Attainment at 8 mcg/ml [ Time Frame: 24 hours ]
    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.

  2. Safety and Tolerability (Changes in Serum Chemistry, Hematology and Hepatic Lab Values, as Well as Reported Adverse Events) [ Time Frame: 3 days ]
    This outcome will assess the safety and tolerability of ceftolozane/tazobactam in adults with CF after 4-6 doses, as measured by changes in serum chemistry, hematology and hepatic lab values, as well as reported adverse events by patients and providers.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02421120


Locations
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United States, Connecticut
Hartford Hospital
Hartford, Connecticut, United States, 06102
United States, Indiana
Riley Hospital for Children at Indiana University Health
Indianapolis, Indiana, United States, 46202
United States, North Carolina
University of North Carolina Medical Center
Chapel Hill, North Carolina, United States, 27599
United States, Pennsylvania
St. Christopher's Hospital for Children
Philadelphia, Pennsylvania, United States, 19134
Sponsors and Collaborators
Joseph Kuti
Cubist Pharmaceuticals LLC
Indiana University Health
University of North Carolina
St. Christopher's Hospital for Children
Investigators
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Principal Investigator: Joseph L Kuti, PharmD Hartford Hospital

Publications of Results:
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Responsible Party: Joseph Kuti, Associate Director, Clinical and Economic Studies, Hartford Hospital
ClinicalTrials.gov Identifier: NCT02421120    
Other Study ID Numbers: HHC-2015-0107
First Posted: April 20, 2015    Key Record Dates
Results First Posted: April 13, 2017
Last Update Posted: March 19, 2018
Last Verified: February 2018
Additional relevant MeSH terms:
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Pseudomonas Infections
Cystic Fibrosis
Pulmonary Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Gram-Negative Bacterial Infections
Bacterial Infections
Tazobactam
Ceftolozane
Cephalosporins
Ceftolozane, tazobactam drug combination
Penicillanic Acid
Anti-Bacterial Agents
Anti-Infective Agents
beta-Lactamase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents, Urinary
Renal Agents