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)

Phase 1

Completed

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

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

Registration Number: NCT02266706

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

Brief Summary: 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 43

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg	Ceftolozane/Tazobactam 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.
Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC	Ceftolozane/Tazobactam 1000/500 mg	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.
Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg	Ceftolozane/Tazobactam 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.
Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg	Ceftolozane/Tazobactam 12/6 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.
Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg	Ceftolozane/Tazobactam 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.
Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg	Ceftolozane/Tazobactam 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.
Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg	Ceftolozane/Tazobactam 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.
Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg	Ceftolozane/Tazobactam 18/9 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.
Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg	Ceftolozane/Tazobactam 18/9 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.

Primary Outcome Measures

Name	Time	Method
Maximum Plasma Concentration (Cmax) 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.	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 of Last Sampling Point (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.	Blood was collected for the determination of Tlast of ceftolozane.
Time of Last Sampling Point (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.	Blood was collected for the determination of Tlast of tazobactam.
Maximum Plasma Concentration (Cmax) 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.	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.
Time to Maximum Plasma Concentration (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.	Blood was collected for the determination of Tmax of ceftolozane.
Plasma Concentration at the Last Quantifiable Concentration (Clast) 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.	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.
Area Under the Plasma Concentration-Time Curve (AUClast) 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.	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.
Volume of Distribution at Steady State (Vss) 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.	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.
Time to Maximum Plasma Concentration (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.	Blood was collected for the determination of Tmax of tazobactam.
Plasma Concentration at the Last Quantifiable Concentration (Clast) 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.	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.
Area Under the Plasma Concentration-Time Curve (AUClast) 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.	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 (AUC0-inf) 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.	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	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	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	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.
Plasma Clearance (CL) 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.	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	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.
Area Under the Plasma Concentration-Time Curve (AUC0-inf) 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.	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With One or More Adverse Events	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	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.