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

NCT02387372 | Completed Phase 1 Results

• 2 other identifiers: 7625A-007CXA-ICU-14-01
• Study Type: interventional
• Target: 37
• Locations: 0 countries
• Sites: N/A

Brief Summary

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

Conditions

Critically Ill; Pneumonia

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (10)

• Number of Participants With Adverse Events (AEs)

  Up to 5 days

• Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.

  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.

  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.

  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.

  Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion

Study Arms (2)

Mechanically Ventilated

EXPERIMENTAL

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

Critically Ill

EXPERIMENTAL

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

Interventions

Ceftolozane/Tazobactam - Multiple Doses 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

Mechanically Ventilated

Ceftolozane/Tazobactam - Single Dose DRUG

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

Critically Ill

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Related Publications (2)

• 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.

  PMID: 33567333 DERIVED

• 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.

  PMID: 32211756 DERIVED

MeSH Terms

Conditions

Critical Illness; Pneumonia

Interventions

ceftolozane; Tazobactam

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Penicillanic Acid; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Sulfones; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 12, 2015
• First Posted: March 13, 2015
• Study Start: February 5, 2015
• Primary Completion: June 15, 2017
• Study Completion: June 16, 2017
• Last Updated: August 28, 2019
• Results First Posted: February 15, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will share