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
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 43
- 主要终点
- Maximum Plasma Concentration (Cmax) of Tazobactam
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 7 Days 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Ceftolozane/Tazobactam 1000/500 mg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 18/9 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 30/15 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 18/9 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 30/15 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 18/9 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 20/10 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 20/10 mg/kg (Drug)
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.
干预措施: Ceftolozane/Tazobactam 12/6 mg/kg (Drug)
结局指标
主要结局
Maximum Plasma Concentration (Cmax) of Tazobactam
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- Number of Participants With One or More Adverse Events(Up to Day 10)
- Number of Participants Who Discontinued the Study Due to an Adverse Event(Up to Day 10)