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

• Sponsor: Joseph L. Kuti, PharmD (Other)
• Overall Status: Completed
• CT.gov ID: NCT02421120
• Collaborator: Cubist Pharmaceuticals LLC (Industry), Indiana University Health (Other), University of North Carolina (Other), St. Christopher's Hospital for Children (Other)
• Enrollment: 21
• Locations: 4
• Arm: 1
• Duration (Months): 13
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• 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: Sep 1, 2015
• Actual Primary Completion Date: Mar 1, 2016
• Actual Study Completion Date: Oct 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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 Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hartford Hospital	Hartford	Connecticut	United States	06102
2	Riley Hospital for Children at Indiana University Health	Indianapolis	Indiana	United States	46202
3	University of North Carolina Medical Center	Chapel Hill	North Carolina	United States	27599
4	St. Christopher's Hospital for Children	Philadelphia	Pennsylvania	United States	19134

Sponsors and Collaborators

• Joseph L. Kuti, PharmD
• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Joseph L. Kuti, PharmD, Associate Director, Clinical and Economic Studies, Hartford Hospital
• ClinicalTrials.gov Identifier: NCT02421120
• Other Study ID Numbers: HHC-2015-0107
• First Posted: Apr 20, 2015
• Last Update Posted: Aug 4, 2020
• Last Verified: Jul 1, 2020

• Additional relevant MeSH terms: Pseudomonas Infections; Cystic Fibrosis; Pulmonary Fibrosis; Fibrosis; Tazobactam; Ceftolozane; Ceftolozane, tazobactam drug combination

Study Results

Participant Flow

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Period Title: Overall Study
STARTED	21
COMPLETED	20
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Overall Participants	20
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	25.4
Sex: Female, Male (Count of Participants)
Female	14 70%
Male	6 30%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	20 100%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	53.2 (8.2)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	161.8 (8.29)
Creatinine Clearance (milliliters per minute) [Mean (Full Range) ]
Mean (Full Range) [milliliters per minute]	117.7

Outcome Measures

1. Primary Outcome

Title	Ceftolozane Clearance
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Measure Participants	20
Mean (Standard Deviation) [Liters per hour]	4.76 (1.13)

2. Primary Outcome

Title	Ceftolozane Volume of Distribution (Central Compartment)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Measure Participants	20
Mean (Standard Deviation) [Liters]	7.51 (2.05)

3. Primary Outcome

Title	Tazobactam Clearance
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Measure Participants	20
Mean (Standard Deviation) [Liters per hour]	20.51 (4.41)

4. Primary Outcome

Title	Tazobactam Volume of Distribution (Central Compartment)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Measure Participants	20
Mean (Standard Deviation) [Liters]	7.85 (2.66)

5. Secondary Outcome

Title	Ceftolozane Probability of Target Attainment at 8 mcg/ml
Description	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

Outcome Measure Data

Analysis Population Description

The results of this analysis are based on 5000 simulated patients with the same pharmacokinetics to the 20 enrolled participants.

Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
Measure Participants	20
Number [percent of simulated population]	97.1

Adverse Events

Time Frame	Adverse events were collected over the course of the 3 day study.
Adverse Event Reporting Description	Laboratory (chemistry, complete blood count, liver function tests, urinalysis) were completed systematically prior to first dose and within 24 hours after completion of the final pharmacokinetic blood sample. All other adverse events collected when reported by the participant or during daily physical examination.
Arm/Group Title	Ceftolozane/Tazobactam
Arm/Group Description	Ceftolozane/Tazobactam 3 grams every 8 hours intravenously for 4-6 doses Ceftolozane/Tazobactam: 1 hour intravenous infusion
All Cause Mortality
	Ceftolozane/Tazobactam
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Serious Adverse Events
	Ceftolozane/Tazobactam
	Affected / at Risk (%)	# Events
Total	0/21 (0%)
Other (Not Including Serious) Adverse Events
	Ceftolozane/Tazobactam
	Affected / at Risk (%)	# Events
Total	4/21 (19%)
General disorders
Hypokalemia	2/21 (9.5%)	2
Hepatobiliary disorders
Liver Function Test Elevation	1/21 (4.8%)	1
Reproductive system and breast disorders
Vaginal Itching	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Type I Hypersensitivity Reaction	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
Erythema	1/21 (4.8%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.