Pharmacokinetic and Safety Study of Ceftolozane/Tazobactam in Pediatric Participants Receiving Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis (MK-7625A-010)

Overview

The purpose of this study was to assess the pharmacokinetics, safety, and tolerability of a single intravenous dose of ceftolozane/tazobactam (MK-7625A) in pediatric participants. In each of the 6 age cohorts, an interim analysis of pharmacokinetics (PK) and safety data was conducted after approximately 3 participants had received the initially proposed dose. The interim analysis was to determine whether the initial dose was appropriate based on pre-defined criteria. If data from the interim analysis demonstrated that the initially proposed dose met the above criteria, enrollment was to continue with the same dose administered to approximately 3 additional participants of the same age range. However, if the interim analysis demonstrated that a new optimized dose was required, the new dose was to be administered to approximately 3 additional participants of the same age range.

Full Title of Study: “A Phase 1, Non-comparative, Open-label Study to Characterize the Pharmacokinetics of a Single Intravenous Dose of Ceftolozane/Tazobactam in Pediatric Patients Receiving Standard of Care Antibiotic Therapy for Proven or Suspected Gram-negative Infection or for Peri-operative Prophylaxis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: June 8, 2017

Interventions

  • Drug: Ceftolozane/Tazobactam 1000/500 mg
    • A fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.
  • Drug: Ceftolozane/Tazobactam 30/15 mg/kg
    • A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.
  • Drug: Ceftolozane/Tazobactam 20/10 mg/kg
    • A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.
  • Drug: Ceftolozane/Tazobactam 18/9 mg/kg
    • A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.
  • Drug: Ceftolozane/Tazobactam 12/6 mg/kg
    • A FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute infusion.

Arms, Groups and Cohorts

  • Experimental: Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC
    • Participants ≥12 to <18 years of age received a single dose of ceftolozane/tazobactam (TOL/TAZ) 1000/500 mg FDC as a 60-minute infusion on Day 1.
  • Experimental: Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg
    • Participants ≥7 to <12 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1.
  • Experimental: Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg
    • Participants ≥2 to <7 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg.
  • Experimental: Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg
    • Participants ≥3 months to <2 years of age received a single dose of TOL/TAZ 18/9 mg/kg as a 60-minute infusion on Day 1. Participants in this cohort enrolled after interim analysis for Cohort 3 received TOL/TAZ 30/15 mg/kg.
  • Experimental: Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg
    • Participants from birth (>32 weeks gestation, 7 days postnatal) to <3 months of age received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 mg/kg was changed to TOL/TAZ 20/10.
  • Experimental: Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg
    • Participants from birth (≤32 weeks gestation, 7 days postnatal) to <3 months of age with creatinine clearance =20 – 49 mL/min/1.73 m^2 received a single dose of TOL/TAZ 12/6 mg/kg as a 60-minute infusion on Day 1; participants with creatinine clearance ≥50 mL/min/1.73 m^2 received a single dose of TOL/TAZ 20/10 mg/kg as a 60-minute infusion on Day 1. After interim analysis for Cohort 4, the original regimen of TOL/TAZ 12/6 was changed to TOL/TAZ 20/10 mg/kg for participants with creatinine clearance ≥50 mL/min/1.73 m^2.

Clinical Trial Outcome Measures

Primary Measures

  • Maximum Plasma Concentration (Cmax) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Cmax of ceftolozane. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Maximum Plasma Concentration (Cmax) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Cmax of tazobactam. Cmax is expressed as geometric least-squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Time to Maximum Plasma Concentration (Tmax) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Tmax of ceftolozane.
  • Time to Maximum Plasma Concentration (Tmax) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Tmax of tazobactam.
  • Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Clast of ceftolozane. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Clast of tazobactam. Clast is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Time of Last Sampling Point (Tlast) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Tlast of ceftolozane.
  • Time of Last Sampling Point (Tlast) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Tlast of tazobactam.
  • Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of ceftolozane. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of AUC from time zero to the last quantifiable concentration of tazobactam. AUC0-last is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of AUC from time zero extrapolated to infinity of ceftolozane. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of AUC from time zero extrapolated to infinity of tazobactam. AUC0-inf is expressed as geometric least squares mean and confidence interval based on back-transformed least-squares mean and confidence interval from linear mixed-effects model with group fixed effect performed on natural log-transformed values.
  • Elimination Half-life (t1/2) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of t1/2 of ceftolozane. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Elimination Half-life (t1/2) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of t1/2 of tazobactam. t1/2 is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Volume of Distribution at Steady State (Vss) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Vss of ceftolozane. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Volume of Distribution at Steady State (Vss) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of Vss of tazobactam. Vss is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Plasma Clearance (CL) of Ceftolozane
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of CL of ceftolozane. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.
  • Plasma Clearance (CL) of Tazobactam
    • Time Frame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
    • Blood was collected for the determination of CL of tazobactam. CL is expressed as geometric mean and percent geometric coefficient of variation, CV% = 100*sqrt(exp(s^2)-1), where s^2 is the observed between-subjects variance on the natural log-scale.

Secondary Measures

  • Number of Participants With One or More Adverse Events
    • Time Frame: Up to Day 10
    • An adverse event (AE) is any untoward medical occurrence in a study 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, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.
  • Number of Participants Who Discontinued the Study Due to an Adverse Event
    • Time Frame: Up to Day 10
    • An adverse event (AE) is any untoward medical occurrence in a study 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, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product.

Participating in This Clinical Trial

Key Inclusion Criteria:

1. Males or non-pregnant females from birth to <18 years of age 2. Receiving standard of care antibiotic therapy for suspected or diagnosed Gram-negative infection or for peri-operative prophylaxis 3. Groups 1-4: Calculated creatinine clearance rate (CLCR) ≥ 80 ml/min/1.73m2 at baseline 4. Group 5: CLCR ≥ 50 ml/min/1.73m2 at baseline 5. Group 6: CLCR ≥ 20 ml/min/1.73m2 at baseline Key Exclusion Criteria:

1. Known allergy/hypersensitivity to any β-lactam antibacterial 2. History of clinically significant renal, hepatic, or hemodynamic instability 3. Planned use of cardiopulmonary bypass or dialysis 4. Planned blood transfusion within 24 hours of study drug administration 5. Clinically significant abnormal laboratory test results not related to the underlying infection 6. Receipt of piperacillin/tazobactam within 24 hours of study drug administration 7. Likely to be at risk of hemodynamic disturbance following collection of the required PK blood samples

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 17 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Cubist Pharmaceuticals LLC
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Medical Director, Study Director, Merck Sharp & Dohme Corp.

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