Safety and Pharmacokinetics of Ceftolozane/Tazobactam in Pediatric Participants With Nosocomial Pneumonia (MK-7625A-036)

Study Overview
=================
Brief Summary
-----------------
This is a phase 1, open-label, non-comparative, multicenter clinical study to evaluate the safety, tolerability, and pharmacokinetics of ceftolozane/tazobactam (MK-7625A) in pediatric participants with nosocomial pneumonia (NP).

Official Title
-----------------
A Phase 1, Open-label, Non-comparative, Multicenter Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Ceftolozane/Tazobactam (MK-7625A) in Pediatric Participants With Nosocomial Pneumonia

Conditions
-----------------
Nosocomial Pneumonia

Intervention / Treatment
-----------------
* Drug: Ceftolozane/Tazobactam


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is hospitalized and anticipated to receive a minimum of 8 days of concomitant standard-of-care [SOC] antibiotic therapy for proven or suspected NP. If male, is abstinent from heterosexual intercourse, or agrees to use contraception during the intervention period and for ≥30 days after the last dose of study intervention. If female, is not pregnant or breastfeeding, or is not a woman of childbearing potential (WOCBP), or is a WOCBP using acceptable contraception, is a WOCBP with negative urine or serum pregnancy test within 48 hours of the first dose of study intervention, or is abstinent from heterosexual intercourse. Exclusion Criteria: Has a documented history of any moderate or severe hypersensitivity (or allergic) reaction to any β-lactam antibacterial. Participants 3 months to <18 years of age: has moderate to severe impairment of renal function, defined as an estimated creatinine clearance (CrCL) <50 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration. Participants <3 months of age: has CrCL <20 mL/min/1.73 m2 based on the revised Schwartz equation or requirement for peritoneal dialysis, hemodialysis, or hemofiltration. Is receiving or is anticipated to receive piperacillin/tazobactam while receiving ceftolozane/tazobactam or has received piperacillin/tazobactam within 24 hours prior to the first dose of ceftolozane/tazobactam. Has participated in any clinical study of a therapeutic investigational product within 30 days prior to the first dose of ceftolozane/tazobactam. Has previous participation in any study of ceftolozane or ceftolozane/tazobactam. Has any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the participant or the quality of study data. Has any rapidly progressing disease or immediately life-threatening illness including acute hepatic failure or septic shock. Has active immunosuppression.

Ages Eligible for Study
-----------------
Minimum Age: 7 Days
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Ceftolozane/Tazobactam 12 to <18 Years of Age<br>Participants 12 to <18 years of age with nosocomial pneumonia receive intravenous (IV) ceftolozane/tazobactam every 8 hours for 8-14 days. | Drug: Ceftolozane/Tazobactam<br>* Participants 12 to <18 years of age: IV ceftolozane 2 g with tazobactam 1 g infused over a 60-minute period. Participants <12 years of age: IV ceftolozane 40 mg/kg with tazobactam 20 mg/kg infused over a 60-minute period (not to exceed a dose of ceftolozane 2g and tazobactam 1 g).<br>* Other names: MK-7625A;|
| Experimental: Group 2: Ceftolozane/Tazobactam 7 to <12 Years of Age<br>Participants 7 to <12 years of age with nosocomial pneumonia receive IV ceftolozane/tazobactam every 8 hours for 8-14 days. | Drug: Ceftolozane/Tazobactam<br>* Participants 12 to <18 years of age: IV ceftolozane 2 g with tazobactam 1 g infused over a 60-minute period. Participants <12 years of age: IV ceftolozane 40 mg/kg with tazobactam 20 mg/kg infused over a 60-minute period (not to exceed a dose of ceftolozane 2g and tazobactam 1 g).<br>* Other names: MK-7625A;|
| Experimental: Group 3: Ceftolozane/Tazobactam 2 to <7 Years of Age<br>Participants 2 to <7 years of age with nosocomial pneumonia receive IV ceftolozane/tazobactam every 8 hours for 8-14 days. | Drug: Ceftolozane/Tazobactam<br>* Participants 12 to <18 years of age: IV ceftolozane 2 g with tazobactam 1 g infused over a 60-minute period. Participants <12 years of age: IV ceftolozane 40 mg/kg with tazobactam 20 mg/kg infused over a 60-minute period (not to exceed a dose of ceftolozane 2g and tazobactam 1 g).<br>* Other names: MK-7625A;|
| Experimental: Group 4: Ceftolozane/Tazobactam 3 Months to <2 Years of Age<br>Participants 3 months to <2 years of age with nosocomial pneumonia receive IV ceftolozane/tazobactam every 8 hours for 8-14 days. | Drug: Ceftolozane/Tazobactam<br>* Participants 12 to <18 years of age: IV ceftolozane 2 g with tazobactam 1 g infused over a 60-minute period. Participants <12 years of age: IV ceftolozane 40 mg/kg with tazobactam 20 mg/kg infused over a 60-minute period (not to exceed a dose of ceftolozane 2g and tazobactam 1 g).<br>* Other names: MK-7625A;|
| Experimental: Group 5: Ceftolozane/Tazobactam Birth to <3 Months of Age<br>Participants from birth to <3 months of age with nosocomial pneumonia receive IV ceftolozane/tazobactam every 8 hours for 8-14 days. | Drug: Ceftolozane/Tazobactam<br>* Participants 12 to <18 years of age: IV ceftolozane 2 g with tazobactam 1 g infused over a 60-minute period. Participants <12 years of age: IV ceftolozane 40 mg/kg with tazobactam 20 mg/kg infused over a 60-minute period (not to exceed a dose of ceftolozane 2g and tazobactam 1 g).<br>* Other names: MK-7625A;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with any adverse events (AEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 31 days | 
| Percentage of participants with any serious AEs (SAEs) | An SAE is any untoward medical consequence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongs existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other important medical event. | Up to 31 days | 
| Percentage of participants with any drug-related AEs | A drug-related AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, and considered related to the study intervention. | Up to 31 days | 
| Percentage of participants with any drug-related SAEs | A drug-related SAE is any untoward medical consequence that, at any dose, results in death, is life-threatening, requires inpatient hospitalization or prolongs existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or any other important medical event, that is considered related to the study intervention. | Up to 31 days | 
| Percentage of participants with AEs leading to discontinuation of study intervention | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of ceftolozane | The plasma concentrations of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma ceftolozane | The plasma AUC0-8 of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Area under the concentration-time curve of an 8-hour dosing interval (AUC0-8) of plasma tazobactam | The plasma AUC0-8 of tazobactam will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Maximum observed concentration during a dosage interval (Cmax) of plasma ceftolozane | The plasma Cmax of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Maximum observed concentration during a dosage interval (Cmax) of plasma tazobactam | The plasma Cmax of tazobactam will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Elimination half-life (t1/2) of plasma ceftolozane | The plasma t1/2 of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Elimination half-life (t1/2) of plasma tazobactam | The plasma t1/2 of tazobactam will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Volume of distribution (Vd) of plasma ceftolozane | The plasma Vd of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Volume of distribution (Vd) of plasma tazobactam | The plasma Vd of tazobactam will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Clearance (CL) of plasma ceftolozane | The plasma CL of ceftolozane will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion | 
| Clearance (CL) of plasma tazobactam | The plasma CL of tazobactam will be determined in each group. | Day 3: 1, between 4-5, and between 7-8 hours after start of infusion |