Cystic Fibrosis, Cystic Fibrosis Pulmonary Exacerbation, Pseudomonas Aeruginosa Infection
Conditions
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.
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.
Interventions
1 hour intravenous infusion
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Indiana University Health
University of North Carolina
St. Christopher's Hospital for Children
Joseph L. Kuti, PharmD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ceftolozane Clearance | 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. |
| Ceftolozane Volume of Distribution (Central Compartment) | 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. |
| Tazobactam Clearance | 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. |
| Tazobactam Volume of Distribution (Central Compartment) | 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
| Measure | Time frame | Description |
|---|---|---|
| Ceftolozane Probability of Target Attainment at 8 mcg/ml | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ceftolozane/Tazobactam Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses
Ceftolozane/Tazobactam: 1 hour intravenous infusion | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Ceftolozane/Tazobactam |
|---|---|
| Age, Continuous | 25.4 years |
| Creatinine Clearance | 117.7 milliliters per minute |
| Height | 161.8 centimeters STANDARD_DEVIATION 8.29 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 53.2 kilograms STANDARD_DEVIATION 8.2 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 21 |
| other Total, other adverse events | 4 / 21 |
| serious Total, serious adverse events | 0 / 21 |
Outcome results
Primary
Ceftolozane Clearance
This outcome determines the clearance of ceftolozane over the 8 hour dosing interval.
Time frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftolozane/Tazobactam | Ceftolozane Clearance | 4.76 Liters per hour | Standard Deviation 1.13 |
Primary
Ceftolozane Volume of Distribution (Central Compartment)
This outcome determines the volume of distribution of ceftolozane over the 8 hour dosing interval.
Time frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftolozane/Tazobactam | Ceftolozane Volume of Distribution (Central Compartment) | 7.51 Liters | Standard Deviation 2.05 |
Primary
Tazobactam Clearance
This outcome determines the clearance of tazobactam over the 8 hour dosing interval.
Time frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftolozane/Tazobactam | Tazobactam Clearance | 20.51 Liters per hour | Standard Deviation 4.41 |
Primary
Tazobactam Volume of Distribution (Central Compartment)
This outcome determines the volume of distribution of tazobactam over the 8 hour dosing interval.
Time frame: 0, 1-1.08, 1.25-1.5, 2-3, 4-5, and 7-8 hours after start of final dose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ceftolozane/Tazobactam | Tazobactam Volume of Distribution (Central Compartment) | 7.85 Liters | Standard Deviation 2.66 |
Secondary
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.
Time frame: 24 hours
Population: The results of this analysis are based on 5000 simulated patients with the same pharmacokinetics to the 20 enrolled participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ceftolozane/Tazobactam | Ceftolozane Probability of Target Attainment at 8 mcg/ml | 97.1 percent of simulated population |