Peri-operative Prophylaxis, Proven or Suspected Gram-negative Bacterial Infection
Conditions
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.
Interventions
DRUGCeftolozane/Tazobactam 1000/500 mg
A fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.
DRUGCeftolozane/Tazobactam 30/15 mg/kg
A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.
DRUGCeftolozane/Tazobactam 20/10 mg/kg
A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.
DRUGCeftolozane/Tazobactam 18/9 mg/kg
A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.
DRUGCeftolozane/Tazobactam 12/6 mg/kg
A FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute infusion.
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Days to 17 Years
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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 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. |
| 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 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. |
| 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. |
| 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. |
| 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 (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. |
| 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. |
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Participant flow
Recruitment details
Participants were screened for eligibility within 48 hours prior to study drug administration.
Pre-assignment details
After interim analysis, dose level adjustments were made to some groups based on safety and pharmacokinetics targets. Thus, the initial 6 cohorts were expanded to a total of 9 cohorts for analysis.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 6 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg Participants ≥7 to \<12 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1. | 7 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg Participants ≥2 to \<7 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1. | 4 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg Participants ≥2 to \<7 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1. | 4 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg Participants ≥3 months to \<2 years of age received a single dose of ceftolozane/tazobactam 18/9 mg/kg as a 60-minute infusion on Day 1. | 1 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg Participants ≥3 months to \<2 years of age received a single dose of ceftolozane/tazobactam 30/15 mg/kg as a 60-minute infusion on Day 1. | 7 |
| 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 ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1. | 8 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg Participants from birth (≤32 weeks gestation, 7 days postnatal) to \<3 months of age with creatinine clearance of 20 - 49 mL/min/1.73 m\^2 received a single dose of ceftolozane/tazobactam 12/6 mg/kg as a 60-minute infusion on Day 1. | 2 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg Participants from birth (≤32 weeks gestation, 7 days postnatal) to \<3 months of age with creatinine clearance ≥50 mL/min/1.73 m\^2 received a single dose of ceftolozane/tazobactam 20/10 mg/kg as a 60-minute infusion on Day 1. | 4 |
| Total | 43 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Enrollment in another study | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Screen failure | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 4.8 Years STANDARD_DEVIATION 5.6 | 8.5 Years STANDARD_DEVIATION 1.2 | 5.5 Years STANDARD_DEVIATION 0.8 | 4.8 Years STANDARD_DEVIATION 1.8 | 0.9 Years STANDARD_DEVIATION 0 | 16.1 Years STANDARD_DEVIATION 1.4 | 0.9 Years STANDARD_DEVIATION 0.7 | 0.1 Years STANDARD_DEVIATION 0 | 0.1 Years STANDARD_DEVIATION 0 | 0.2 Years STANDARD_DEVIATION 0.1 |
| Age, Customized Adolescents (12-17 years) | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Children (2-11 years) | 16 Participants | 7 Participants | 4 Participants | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 19 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 6 Participants | 6 Participants | 2 Participants | 4 Participants |
| Age, Customized Newborns (0-27days) | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 8 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Other | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 7 Participants | 4 Participants | 2 Participants | 0 Participants | 5 Participants | 6 Participants | 7 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 22 Participants | 3 Participants | 2 Participants | 3 Participants | 0 Participants | 5 Participants | 2 Participants | 4 Participants | 0 Participants | 3 Participants |
| Sex: Female, Male Male | 21 Participants | 4 Participants | 2 Participants | 1 Participants | 1 Participants | 1 Participants | 5 Participants | 4 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 6 | 0 / 3 | 0 / 3 | 0 / 1 | 0 / 5 | 0 / 7 | 0 / 2 | 0 / 4 |
| other Total, other adverse events | 2 / 6 | 0 / 6 | 1 / 3 | 1 / 3 | 1 / 1 | 1 / 5 | 1 / 7 | 2 / 2 | 0 / 4 |
| serious Total, serious adverse events | 1 / 6 | 1 / 6 | 0 / 3 | 0 / 3 | 0 / 1 | 1 / 5 | 0 / 7 | 0 / 2 | 0 / 4 |
Outcome results
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 133 Hours*μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 107 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 99.4 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 186 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 103 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 202 Hours*μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 164 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 165 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane | 137 Hours*μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 17.5 Hours*μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 10.2 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 17.8 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 28.9 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 14.9 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 29.9 Hours*μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 24.9 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 77.6 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam | 22.3 Hours*μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 124 Hours*μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 102 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 94.2 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 172 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 98.8 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 178 Hours*μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 131 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 118 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane | 119 Hours*μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 17.3 Hours*μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 9.69 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 17.6 Hours*μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 28.5 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 14.8 Hours*μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 28.9 Hours*μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 21.3 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 21.6 Hours*μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam | 21.9 Hours*μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Elimination Half-life (t1/2) of Ceftolozane | 1.45 Hours | Geometric Coefficient of Variation 16.7 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.29 Hours | Geometric Coefficient of Variation 9.6 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.34 Hours | Geometric Coefficient of Variation 14 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.48 Hours | Geometric Coefficient of Variation 35.5 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.30 Hours | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.63 Hours | Geometric Coefficient of Variation 69 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 2.21 Hours | Geometric Coefficient of Variation 37.6 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 3.14 Hours | Geometric Coefficient of Variation 0.9 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Elimination Half-life (t1/2) of Ceftolozane | 1.73 Hours | Geometric Coefficient of Variation 29.7 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Elimination Half-life (t1/2) of Tazobactam | 0.702 Hours | Geometric Coefficient of Variation 38.7 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.544 Hours | Geometric Coefficient of Variation 3.1 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.719 Hours | Geometric Coefficient of Variation 29.7 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.770 Hours | Geometric Coefficient of Variation 34.2 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.538 Hours | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.815 Hours | Geometric Coefficient of Variation 85.1 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 1.09 Hours | Geometric Coefficient of Variation 32 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 3.03 Hours | — |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Elimination Half-life (t1/2) of Tazobactam | 0.875 Hours | Geometric Coefficient of Variation 20.4 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Maximum Plasma Concentration (Cmax) of Ceftolozane | 63.5 μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 56.2 μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 51.4 μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 96.6 μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 50.5 μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 91.3 μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 45.0 μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 34.9 μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Maximum Plasma Concentration (Cmax) of Ceftolozane | 45.2 μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Maximum Plasma Concentration (Cmax) of Tazobactam | 14.0 μg/mL |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 9.25 μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 15.7 μg/mL |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 24.8 μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 11.6 μg/mL |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 22.4 μg/mL |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 11.7 μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 6.87 μg/mL |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Maximum Plasma Concentration (Cmax) of Tazobactam | 12.1 μg/mL |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Plasma Clearance (CL) of Ceftolozane | 0.146 L/hour/kg | Geometric Coefficient of Variation 27 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.168 L/hour/kg | Geometric Coefficient of Variation 21.3 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.181 L/hour/kg | Geometric Coefficient of Variation 3.8 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.162 L/hour/kg | Geometric Coefficient of Variation 31.1 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.176 L/hour/kg | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.149 L/hour/kg | Geometric Coefficient of Variation 43.2 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.118 L/hour/kg | Geometric Coefficient of Variation 36 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.0723 L/hour/kg | Geometric Coefficient of Variation 32.2 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Clearance (CL) of Ceftolozane | 0.147 L/hour/kg | Geometric Coefficient of Variation 6.8 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Plasma Clearance (CL) of Tazobactam | 0.556 L/hour/kg | Geometric Coefficient of Variation 53.9 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.886 L/hour/kg | Geometric Coefficient of Variation 23.1 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.506 L/hour/kg | Geometric Coefficient of Variation 42 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.519 L/hour/kg | Geometric Coefficient of Variation 44.8 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.611 L/hour/kg | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.502 L/hour/kg | Geometric Coefficient of Variation 34.7 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.385 L/hour/kg | Geometric Coefficient of Variation 34.1 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.0760 L/hour/kg | — |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Clearance (CL) of Tazobactam | 0.452 L/hour/kg | Geometric Coefficient of Variation 24.9 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 4.01 μg/mL | Geometric Coefficient of Variation 40.4 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 2.85 μg/mL | Geometric Coefficient of Variation 37.3 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 2.47 μg/mL | Geometric Coefficient of Variation 29.1 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 5.69 μg/mL | Geometric Coefficient of Variation 59.5 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 2.53 μg/mL | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 5.72 μg/mL | Geometric Coefficient of Variation 96.1 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 8.70 μg/mL | Geometric Coefficient of Variation 49.1 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 10.2 μg/mL | Geometric Coefficient of Variation 49.2 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane | 6.26 μg/mL | Geometric Coefficient of Variation 39.2 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.232 μg/mL | Geometric Coefficient of Variation 52.2 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.420 μg/mL | Geometric Coefficient of Variation 188.6 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.137 μg/mL | Geometric Coefficient of Variation 24.1 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.327 μg/mL | Geometric Coefficient of Variation 62.7 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.224 μg/mL | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.401 μg/mL | Geometric Coefficient of Variation 90.5 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.657 μg/mL | Geometric Coefficient of Variation 169.2 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 3.66 μg/mL | Geometric Coefficient of Variation 57.6 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam | 0.266 μg/mL | Geometric Coefficient of Variation 81.3 |
Primary
Time of Last Sampling Point (Tlast) of Ceftolozane
Blood was collected for the determination of 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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.00 Hours |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.01 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.08 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 5.77 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.00 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.00 Hours |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.01 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 6.40 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time of Last Sampling Point (Tlast) of Ceftolozane | 5.85 Hours |
Primary
Time of Last Sampling Point (Tlast) of Tazobactam
Blood was collected for the determination of 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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Time of Last Sampling Point (Tlast) of Tazobactam | 4.15 Hours |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 3.10 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 5.85 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 5.72 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 4.00 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 5.02 Hours |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 5.95 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 6.40 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time of Last Sampling Point (Tlast) of Tazobactam | 5.85 Hours |
Primary
Time to Maximum Plasma Concentration (Tmax) of Ceftolozane
Blood was collected for the determination of 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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.02 Hours |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.07 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.02 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.03 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.00 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.05 Hours |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.08 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.80 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Ceftolozane | 1.07 Hours |
Primary
Time to Maximum Plasma Concentration (Tmax) of Tazobactam
Blood was collected for the determination of 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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.00 Hours |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.07 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.02 Hours |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.03 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.00 Hours |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.05 Hours |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.08 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 3.89 Hours |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Time to Maximum Plasma Concentration (Tmax) of Tazobactam | 1.07 Hours |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.274 L/kg | Geometric Coefficient of Variation 25.7 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.296 L/kg | Geometric Coefficient of Variation 22 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.331 L/kg | Geometric Coefficient of Variation 15.6 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.312 L/kg | Geometric Coefficient of Variation 19.5 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.282 L/kg | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.340 L/kg | Geometric Coefficient of Variation 21.1 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.394 L/kg | Geometric Coefficient of Variation 12.6 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.344 L/kg | Geometric Coefficient of Variation 36.6 |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Volume of Distribution at Steady State (Vss) of Ceftolozane | 0.388 L/kg | Geometric Coefficient of Variation 26.9 |
Primary
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.
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.
Population: The pharmacokinetics population included enrolled participants who received a full dose of study drug and had blood samples with quantifiable plasma levels at Cmax and at least 2 time points after Cmax, and were evaluable for the outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.474 L/kg | Geometric Coefficient of Variation 69.6 |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.740 L/kg | Geometric Coefficient of Variation 30.2 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.488 L/kg | Geometric Coefficient of Variation 32 |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.513 L/kg | Geometric Coefficient of Variation 49.2 |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.421 L/kg | — |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.574 L/kg | Geometric Coefficient of Variation 36.2 |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.668 L/kg | Geometric Coefficient of Variation 19.8 |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.338 L/kg | — |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Volume of Distribution at Steady State (Vss) of Tazobactam | 0.667 L/kg | Geometric Coefficient of Variation 29.3 |
Secondary
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.
Time frame: Up to Day 10
Population: The safety population was all enrolled participants who received study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Number of Participants Who Discontinued the Study Due to an Adverse Event | 0 Participants |
Secondary
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.
Time frame: Up to Day 10
Population: The safety population was all enrolled participants who received study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: ≥12 to <18 Years TOL/TAZ 1000/500 mg FDC | Number of Participants With One or More Adverse Events | 2 Participants |
| Cohort 2: ≥7 to <12 Years TOL/TAZ 18/9 mg/kg | Number of Participants With One or More Adverse Events | 1 Participants |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 18/9 mg/kg | Number of Participants With One or More Adverse Events | 1 Participants |
| Cohort 3: ≥2 to <7 Years TOL/TAZ 30/15 mg/kg | Number of Participants With One or More Adverse Events | 1 Participants |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 18/9 mg/kg | Number of Participants With One or More Adverse Events | 1 Participants |
| Cohort 4: ≥3 Months to <2 Years TOL/TAZ 30/15 mg/kg | Number of Participants With One or More Adverse Events | 2 Participants |
| Cohort 5: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Number of Participants With One or More Adverse Events | 1 Participants |
| Cohort 6: Birth to <3 Months TOL/TAZ 12/6 mg/kg | Number of Participants With One or More Adverse Events | 2 Participants |
| Cohort 6: Birth to <3 Months TOL/TAZ 20/10 mg/kg | Number of Participants With One or More Adverse Events | 0 Participants |