Plasma Pharmacokinetics (PK) & Lung Penetration of Ceftolozane/Tazobactam in Participants With Pneumonia (MK-7625A-007)

NCT ID: NCT02387372

Last Updated: 2019-08-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-02-05
• Study Completion Date: 2017-06-16

Brief Summary

The purpose of this study is to evaluate the pharmacokinetics and lung penetration of intravenous Ceftolozane/tazobactam in critically ill participants.

Detailed Description

This is a Phase 1, prospective, multicenter, non-comparative, open-label study to characterize the plasma pharmacokinetics and intrapulmonary penetration of ceftolozane/tazobactam in two groups of participants.

Group 1: approximately 25 ventilated participants with suspected or proven pneumonia receiving concurrent standard antibiotic therapy. Within Group 1, efforts will be made to enroll approximately 5 participants with a CLCR ≥ 150 mL/min (as calculated by the Cockcroft-Gault equation).

Group 2: 8-10 critically ill participants with CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation).

Conditions

Critically Ill; Pneumonia

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Mechanically Ventilated

Participants with proven or suspected pneumonia, undergoing mechanical ventilation will receive 4-6 doses of ceftolozane/tazobactam every 8 hours as a 60-minute intravenous infusion as follows:

• Those with Creatinine clearance (CLCR) > 50 mL/min will receive 4-6 doses of 3 g ceftolozane/tazobactam every 8 hours
• Those with CLCR 30 - 50 mL/min will receive 4-6 doses of 1.5 g ceftolozane/tazobactam every 8 hours
• Those with CLCR 15 - 29 mL/min will receive 6 doses of 750 mg ceftolozane/tazobactam every 8 hours

Group Type: EXPERIMENTAL

Ceftolozane/Tazobactam - Multiple Doses

Intervention Type: DRUG

4-6 doses of ceftolozane/tazobactam every 8 hours as a 60-minute intravenous infusion as follows:

• Participants with CLCR > 50 mL/min will receive 4-6 doses of 3 g ceftolozane/tazobactam every 8 hours
• Participants with CLCR 30 - 50 mL/min will receive 4-6 doses of 1.5 g ceftolozane/tazobactam every 8 hours
• Participants with CLCR 15 - 29 mL/min will receive 6 doses of 750 mg ceftolozane/tazobactam every 8 hours

Critically Ill

Critically ill participants with CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation) will receive a single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion.

Group Type: EXPERIMENTAL

Ceftolozane/Tazobactam - Single Dose

Intervention Type: DRUG

Single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion

Interventions

Ceftolozane/Tazobactam - Multiple Doses

4-6 doses of ceftolozane/tazobactam every 8 hours as a 60-minute intravenous infusion as follows:

• Participants with CLCR > 50 mL/min will receive 4-6 doses of 3 g ceftolozane/tazobactam every 8 hours
• Participants with CLCR 30 - 50 mL/min will receive 4-6 doses of 1.5 g ceftolozane/tazobactam every 8 hours
• Participants with CLCR 15 - 29 mL/min will receive 6 doses of 750 mg ceftolozane/tazobactam every 8 hours

Intervention Type: DRUG

Ceftolozane/Tazobactam - Single Dose

Single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Provide written informed consent prior to any study-related procedure not part of normal medical care.

2. If female,must not be pregnant or nursing, and is either:

1. Not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile due to bilateral tubal ligation, bilateral oophorectomy, or hysterectomy; or

2. Of childbearing potential and:

• Is practicing an effective method of contraception (e.g., oral/parenteral contraceptives or a barrier method) and for at least 1 month prior to baseline assessments, or
• Has a vasectomized partner, or
• Is currently abstinent from sexual intercourse. Participants must be willing to practice the chosen contraceptive method or remain abstinent during the conduct of the study and for at least 30 days after last dose of study medication.

3. Non-vasectomized males are required to practice effective birth control methods (e.g., abstinence, use of a condom or use of other barrier device) during the conduct of the study and for at least 30 days after last dose of study medication;

4. Participants in Group 1 must meet the following criteria:

1. Males or females age 18 years or older;

2. Intubated and on mechanical ventilation for at least 24 hours prior to time of enrollment (includes participants with tracheostomy who are mechanically ventilated);

3. Proven or suspected bacterial pneumonia, as confirmed by the presence of at least one of the prescribed clinical signs and symptoms.

4. Receiving antibiotic therapy for proven or suspected bacterial pneumonia at the time of enrollment and expected to continue on antibiotic therapy while in the study

5. Participants in Group 2 must meet the following criteria:

1. Males or females aged 18 - 54 years;

2. Acute Physiology and Chronic Health Evaluation II (APACHE II) score between 12 and 35, inclusive;

3. CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) within 24 hours of dosing;

4. Documented infection or presumed infection.

Exclusion Criteria

1. Has a documented history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam antibacterial (a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment);

2. Hemoglobin < 7 g/dL at baseline;

3. Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam, probenecid or ceftolozane/tazobactam (non-study use);

4. Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the Investigator);

5. Any condition or circumstance that, in the opinion of the Investigator, would compromise the safety of the participant or the quality of study data;

6. Planned or prior participation in any interventional drug study within the last 30 days;

7. Participants in Group 1 must not meet any of the following criteria:

1. Receipt of effective systemic antibiotic therapy for the treatment of proven or suspected bacterial pneumonia for more than 72 hours prior to start of the first dose of study drug

2. Any of the following diagnoses or conditions that may interfere with the PK assessment/interpretation:

• Cystic fibrosis, acute exacerbation of chronic bronchitis or obstructive airway disease, chronic severe respiratory disease , or active pulmonary tuberculosis,
• Full thickness burns (greater than 15% of total body surface area),
• Lung transplant recipient or donor,
• Any condition or situation where bronchoscopy is not advisable;

8. End-stage renal disease defined as a CLCR < 15 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight), OR requirement for continuous renal replacement therapy or hemodialysis.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

References

Nicolau DP, De Waele J, Kuti JL, Caro L, Larson KB, Yu B, Gadzicki E, Zeng Z, Rhee EG, Rizk ML. Pharmacokinetics and Pharmacodynamics of Ceftolozane/Tazobactam in Critically Ill Patients With Augmented Renal Clearance. Int J Antimicrob Agents. 2021 Apr;57(4):106299. doi: 10.1016/j.ijantimicag.2021.106299. Epub 2021 Feb 7.

Reference Type: DERIVED

PMID: 33567333 (View on PubMed)

Caro L, Nicolau DP, De Waele JJ, Kuti JL, Larson KB, Gadzicki E, Yu B, Zeng Z, Adedoyin A, Rhee EG. Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia. J Antimicrob Chemother. 2020 Jun 1;75(6):1546-1553. doi: 10.1093/jac/dkaa049.

Reference Type: DERIVED

PMID: 32211756 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

CXA-ICU-14-01

Identifier Type: OTHER

Identifier Source: secondary_id

7625A-007

Identifier Type: -

Identifier Source: org_study_id