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

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

Detailed Description
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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).

Official Title
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A 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

Conditions
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Critically Ill, Pneumonia

Intervention / Treatment
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* Drug: Ceftolozane/Tazobactam - Multiple Doses
* Drug: Ceftolozane/Tazobactam - Single Dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent prior to any study-related procedure not part of normal medical care. If female,must not be pregnant or nursing, and is either: 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 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. 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; Participants in Group 1 must meet the following criteria: Males or females age 18 years or older; Intubated and on mechanical ventilation for at least 24 hours prior to time of enrollment (includes participants with tracheostomy who are mechanically ventilated); Proven or suspected bacterial pneumonia, as confirmed by the presence of at least one of the prescribed clinical signs and symptoms. 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 Participants in Group 2 must meet the following criteria: Males or females aged 18 - 54 years; Acute Physiology and Chronic Health Evaluation II (APACHE II) score between 12 and 35, inclusive; CLCR ≥180 mL/min (as calculated by the Cockcroft-Gault equation using actual body weight) within 24 hours of dosing; Documented infection or presumed infection. Exclusion Criteria: 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); Hemoglobin < 7 g/dL at baseline; Prior (within 24 hours of first dose of study drug) or concomitant receipt of piperacillin/tazobactam, probenecid or ceftolozane/tazobactam (non-study use); 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 participant or the quality of study data; Planned or prior participation in any interventional drug study within the last 30 days; Participants in Group 1 must not meet any of the following criteria: 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 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; 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.

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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mechanically Ventilated<br>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<br>* 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<br>|
| Experimental: Critically Ill<br>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<br>* Single dose of ceftolozane/tazobactam, 3 g, as a 60-minute intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for creatinine clearance (CLCR), every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax, maximum plasma concentration, of ceftolozane or tazobactam. Pharmacokinetic (PK) data analysis was performed by non-compartmental analysis (NCA) method using Phoenix WinNonlin version 6.3 or later. | 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 Mechanically Ventilated Participants. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples and epithelial lining fluid (ELF) were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the epithelial lining fluid, ELF to plasma ratio of ceftolozane and tazobactam. | 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 Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax, time of maximum plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast, last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Time of Last Quantifiable Plasma Concentration (Tlast)) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast, time of last quantifiable plasma concentration, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Area Under the Concentration Time Curve (AUC) From the First to Time of the Last Dose (AUC0-last) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last, AUC from the first to time of the last dose, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| AUC From the Time of the Dose to Infinity (AUC0-∞) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞, AUC from the time of the dose to infinity, of ceftolozane or tazobactam. PK data analysis was determined by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the t1/2, terminal elimination half-life, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Volume of Distribution at Steady State (Vss) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss, volume of distribution at steady state, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 
| Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment. | Mechanically ventilated participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL, plasma clearance, of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An adverse event (AE) is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 5 days | 
| Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Cmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion | 
| Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tmax of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Clast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Tlast of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-last of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the AUC0-∞ of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the T1/2 of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the Vss of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | 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. | Critically ill participants received a 60 minute infusion of ceftolozane/tazobactam, adjusted for CLCR, every 8 hours; then blood samples were collected at 1, 2, 4, 6, and 8 hours post start of the final infusion after the last dose of study drug in order to determine the CL of ceftolozane or tazobactam. PK data analysis was performed by NCA method using Phoenix WinNonlin version 6.3 or later. | Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion |