Clinical trial NCT02387372: Plasma Pharmacokinetics (PK) & Lung Penetration of Ceftolozane/Tazobactam in Participants With Pneumonia (MK-7625A-007)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Critically Ill
Pneumonia
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2015-03-13
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
timeFrame: 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.
measure: Epithelial Lining Fluid (ELF) / Plasma Ratio (Intrapulmonary Penetration) of Ceftolozane and Tazobactam Concentrations in Mechanically Ventilated Participants.
timeFrame: Up to Day 2 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of the last infusion.
measure: Time of Maximum Plasma Concentration (Tmax) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
timeFrame: 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.
measure: Last Quantifiable Plasma Concentration (Clast) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
timeFrame: 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.
measure: 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.
timeFrame: 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.
measure: 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.
timeFrame: 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.
measure: 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.
timeFrame: 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.
measure: Terminal Elimination Half-life (t1/2) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
timeFrame: 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.
measure: 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.
timeFrame: 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.
measure: Plasma Clearance (CL) of Ceftolozane or Tazobactam in Mechanically Ventilated Participants for the First and Last Dose of Ceftolozane/Tazobactam Treatment.
timeFrame: 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:
measure: Number of Participants With Adverse Events (AEs)
timeFrame: Up to 5 days
measure: Cmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: Tmax of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: Clast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: Tlast of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: AUC0-last of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: AUC0-∞ of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: T1/2 of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: Vss of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
measure: CL of Ceftolozane/Tazobactam in Critically Ill Participants With Augmented Renal Function.
timeFrame: Day 1 at 0 (pre-dose), 1, 2, 4, 6 and 8 h after the start of infusion
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.