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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Cystic Fibrosis, Cystic Fibrosis Pulmonary Exacerbation, Pseudomonas Aeruginosa Infection

Intervention / Treatment
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* Drug: Ceftolozane/Tazobactam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Documented diagnosis of CF Acute pulmonary exacerbation as the primary reason for admission to the hospital with requirement to receive systemic antibiotic treatment 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: 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) Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam or probenecid History of lung transplant 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 A hemoglobin less than 8 gm/dl at baseline Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator) Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data Planned or prior participation in any other interventional drug study within 30 days

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ceftolozane/Tazobactam<br>Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses | Drug: Ceftolozane/Tazobactam<br>* 1 hour intravenous infusion<br>* Other names: CXA-101;|

What is the study measuring?
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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 |