Clinical trial NCT02266706: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Proven or Suspected Gram-negative Bacterial Infection
Peri-operative Prophylaxis
Lead sponsor: Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Sponsor class: INDUSTRY
First posted: 2014-10-17
Enrollment: 43
Sex: ALL
Minimum age (years): 7
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax) of Ceftolozane
timeFrame: 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.
measure: Maximum Plasma Concentration (Cmax) of Tazobactam
timeFrame: 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.
measure: Time to Maximum Plasma Concentration (Tmax) of Ceftolozane
timeFrame: 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.
measure: Time to Maximum Plasma Concentration (Tmax) of Tazobactam
timeFrame: 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.
measure: Plasma Concentration at the Last Quantifiable Concentration (Clast) of Ceftolozane
timeFrame: 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.
measure: Plasma Concentration at the Last Quantifiable Concentration (Clast) of Tazobactam
timeFrame: 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.
measure: Time of Last Sampling Point (Tlast) of Ceftolozane
timeFrame: 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.
measure: Time of Last Sampling Point (Tlast) of Tazobactam
timeFrame: 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.
measure: Area Under the Plasma Concentration-Time Curve (AUClast) of Ceftolozane
timeFrame: 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.
measure: Area Under the Plasma Concentration-Time Curve (AUClast) of Tazobactam
timeFrame: 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.
measure: Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Ceftolozane
timeFrame: 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.
measure: Area Under the Plasma Concentration-Time Curve (AUC0-inf) of Tazobactam
timeFrame: 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.
measure: Elimination Half-life (t1/2) of Ceftolozane
timeFrame: 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.
measure: Elimination Half-life (t1/2) of Tazobactam
timeFrame: 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.
measure: Volume of Distribution at Steady State (Vss) of Ceftolozane
timeFrame: 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.
measure: Volume of Distribution at Steady State (Vss) of Tazobactam
timeFrame: 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.
measure: Plasma Clearance (CL) of Ceftolozane
timeFrame: 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.
measure: Plasma Clearance (CL) of Tazobactam
timeFrame: Predose and 0.5, 1, 2, 4, and 6 hours after the start of infusion for Cohorts 1 to 4 and 1, 2, and 6 hours after start of infusion for Cohorts 5 and 6.
Secondary outcomes:
measure: Number of Participants With One or More Adverse Events
timeFrame: Up to Day 10
measure: Number of Participants Who Discontinued the Study Due to an Adverse Event
timeFrame: Up to Day 10
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Bradley JS, Ang JY, Arrieta AC, Larson KB, Rizk ML, Caro L, Yang S, Yu B, Johnson MG, Rhee EG. Pharmacokinetics and Safety of Single Intravenous Doses of Ceftolozane/Tazobactam in Children With Proven or Suspected Gram-Negative Infection. Pediatr Infect Dis J. 2018 Nov;37(11):1130-1136. doi: 10.1097/INF.0000000000002170.