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

ID: NCT02387372
Status: Completed
Phase: Phase 1
Start Date: February 05, 2015
First Submitted: January 12, 2015
Last Updated: August 02, 2017
Results: N/A
Sponsors & Collaborators: Cubist Pharmaceuticals LLC
Location: N/A
Conditions: Critically Ill, Pneumonia
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Study Description

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).
Condition or disease Intervention/treatment Phase

Critically Ill

Pneumonia

Drug: Ceftolozane/Tazobactam - Multiple Doses
Other Names
Drug: Ceftolozane/Tazobactam - Single Dose
Other Names
Phase 1

Tracking Information

First Submitted DateJanuary 12, 2015
Last Update Posted DateAugust 02, 2017
Actual Start DateFebruary 05, 2015
Actual Completion DateJune 16, 2017
Actual Primary Completion DateJune 15, 2017
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Maximum concentration (Cmax) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 hours (h) after the start of the first and last infusions.]

  • Epithelial lining fluid (ELF) / plasma ratio (Intrapulmonary penetration) of ceftolozane and tazobactam concentrations in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the last infusion.]

  • Time of maximum concentration (Tmax) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Last quantifiable plasma concentration (Clast) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Time of last quantifiable plasma concentration (Tlast) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Area under the concentration time curve (AUC) from the time of the dose to the Tlast (AUC0-last) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • AUC from the time of the dose to infinity (AUC0-∞) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Terminal elimination half-life (t1/2) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Volume of distribution at steady state (Vss) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

  • Plasma clearance (CL) of ceftolozane/tazobactam in ventilated participants receiving concurrent antibiotic therapy for proven or suspected pneumonia. [Time Frame: Day 1 up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the first and last infusions.]

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Cmax of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • Number of participants with adverse events [Time Frame: Up to 5 days]

  • Tmax of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • Clast of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • Tlast of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • AUC0-last of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • AUC0-∞ of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • T1/2 of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • Vss of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

  • CL of ceftolozane/tazobactam in critically ill participants with augmented renal function. [Time Frame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion]

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitlePlasma Pharmacokinetics (PK) & Lung Penetration of Ceftolozane/Tazobactam in Participants With Pneumonia (MK-7625A-007)
Official TitleA Phase 1, Prospective, Multi-center, Open-label Study to Assess the Plasma Pharmacokinetics and Lung Penetration of Intravenous (IV) Ceftolozane/Tazobactam in Critically Ill Patients
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).

Study TypeInterventional
Study PhasePhase 1
Estimated Enrollment
37
Allocation
Non-Randomized
Interventional Model
Parallel Assignment
Masking
None
Primary Purpose
Treatment
Conditions
Critically Ill
Pneumonia
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: 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

Other Names
Drug: Ceftolozane/Tazobactam - Single Dose

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

Other Names
Study Groups/Cohorts
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

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.

Study Arms
Experimental 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.
Drug : Ceftolozane/Tazobactam - Single Dose
Single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion

Experimental 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
Drug : 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

Arm Intervention/Treatment
Experimental 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.
Drug : Ceftolozane/Tazobactam - Single Dose
Experimental 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
Drug : Ceftolozane/Tazobactam - Multiple Doses

Recruitment Information

Recruitment Status:Completed
Enrollment37
Completion DateJune 16, 2017
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.
GenderAll
Age18 Years to N/A
Accepts Healthy VolunteersNo
Contacts
Not Available
Listed Location Countries
Belgium
France
Germany
Italy
Puerto Rico
Spain
United States

Administrative Information

NCT Number:NCT02387372
Other Study ID Numbers
7625A-007
CXA-ICU-14-01
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
Cubist Pharmaceuticals LLC
Collaborators
Not Available
Investigators
Study Director
Medical Director
Merck Sharp & Dohme Corp.