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)

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Proven or Suspected Gram-negative Bacterial Infection, Peri-operative Prophylaxis

Intervention / Treatment
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* Drug: Ceftolozane/Tazobactam 1000/500 mg
* Drug: Ceftolozane/Tazobactam 30/15 mg/kg
* Drug: Ceftolozane/Tazobactam 20/10 mg/kg
* Drug: Ceftolozane/Tazobactam 18/9 mg/kg
* Drug: Ceftolozane/Tazobactam 12/6 mg/kg


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Males or non-pregnant females from birth to <18 years of age Receiving standard of care antibiotic therapy for suspected or diagnosed Gram-negative infection or for peri-operative prophylaxis Groups 1-4: Calculated creatinine clearance rate (CLCR) ≥ 80 ml/min/1.73m2 at baseline Group 5: CLCR ≥ 50 ml/min/1.73m2 at baseline Group 6: CLCR ≥ 20 ml/min/1.73m2 at baseline Key Exclusion Criteria: Known allergy/hypersensitivity to any β-lactam antibacterial History of clinically significant renal, hepatic, or hemodynamic instability Planned use of cardiopulmonary bypass or dialysis Planned blood transfusion within 24 hours of study drug administration Clinically significant abnormal laboratory test results not related to the underlying infection Receipt of piperacillin/tazobactam within 24 hours of study drug administration Likely to be at risk of hemodynamic disturbance following collection of the required PK blood samples

Ages Eligible for Study
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Minimum Age: 7 Days
Maximum Age: 17 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: Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC<br>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. | Drug: Ceftolozane/Tazobactam 1000/500 mg<br>* A fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.<br>|
| Experimental: Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg<br>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. | Drug: Ceftolozane/Tazobactam 18/9 mg/kg<br>* A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.<br>|
| Experimental: Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg<br>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. | Drug: Ceftolozane/Tazobactam 30/15 mg/kg<br>* A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.<br>Drug: Ceftolozane/Tazobactam 18/9 mg/kg<br>* A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.<br>|
| Experimental: Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg<br>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. | Drug: Ceftolozane/Tazobactam 30/15 mg/kg<br>* A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.<br>Drug: Ceftolozane/Tazobactam 18/9 mg/kg<br>* A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.<br>|
| Experimental: Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg<br>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. | Drug: Ceftolozane/Tazobactam 20/10 mg/kg<br>* A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.<br>|
| Experimental: Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg<br>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. | Drug: Ceftolozane/Tazobactam 20/10 mg/kg<br>* A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.<br>Drug: Ceftolozane/Tazobactam 12/6 mg/kg<br>* A FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute 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 | 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. | 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. | 
| Maximum Plasma Concentration (Cmax) of Tazobactam | 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. | 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. | 
| Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | Blood was collected for the determination of Tmax of ceftolozane. | 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. | 
| Time to Maximum Plasma Concentration (Tmax) of Tazobactam | Blood was collected for the determination of Tmax of tazobactam. | 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. | 
| Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 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. | 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. | 
| Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 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. | 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. | 
| Time of Last Sampling Point (Tlast) of Ceftolozane | Blood was collected for the determination of Tlast of ceftolozane. | 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. | 
| Time of Last Sampling Point (Tlast) of Tazobactam | Blood was collected for the determination of Tlast of tazobactam. | 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. | 
| Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 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. | 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. | 
| Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 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. | 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. | 
| Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 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. | 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. | 
| Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 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. | 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. | 
| Elimination Half-life (t1/2) of Ceftolozane | 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. | 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. | 
| Elimination Half-life (t1/2) of Tazobactam | 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. | 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. | 
| Volume of Distribution at Steady State (Vss) of Ceftolozane | 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. | 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. | 
| Volume of Distribution at Steady State (Vss) of Tazobactam | 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. | 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. | 
| Plasma Clearance (CL) of Ceftolozane | 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. | 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. | 
| Plasma Clearance (CL) of Tazobactam | 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With One or More Adverse Events | 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. | Up to Day 10 | 
| Number of Participants Who Discontinued the Study Due to an Adverse Event | 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. | Up to Day 10 |