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)

NCT02266706 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: 7625A-010CXA-PEDS-13-082014-003485-24MK-7625A-010
• Study Type: interventional
• Target: 43
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Proven or Suspected Gram-negative Bacterial Infection; Peri-operative Prophylaxis

Outcome Measures

Primary Outcomes (18)

• 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.

  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.

• 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.

  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.

• Time to Maximum Plasma Concentration (Tmax) of Ceftolozane

  Blood was collected for the determination of 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.

• Time to Maximum Plasma Concentration (Tmax) of Tazobactam

  Blood was collected for the determination of 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.

• 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.

  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.

• 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.

  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.

• Time of Last Sampling Point (Tlast) of Ceftolozane

  Blood was collected for the determination of 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.

• Time of Last Sampling Point (Tlast) of Tazobactam

  Blood was collected for the determination of 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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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.

• 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.

  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 (2)

• 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

Study Arms (6)

Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 1000/500 mg

Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 18/9 mg/kg

Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 30/15 mg/kg; Drug: Ceftolozane/Tazobactam 18/9 mg/kg

Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 30/15 mg/kg; Drug: Ceftolozane/Tazobactam 18/9 mg/kg

Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 20/10 mg/kg

Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg

EXPERIMENTAL

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.

Drug: Ceftolozane/Tazobactam 20/10 mg/kg; Drug: Ceftolozane/Tazobactam 12/6 mg/kg

Interventions

Ceftolozane/Tazobactam 1000/500 mg DRUG

A fixed dose combination (FDC) of 1000 mg ceftolozane and 500 mg tazobactam as a 60 minute infusion.

Cohort 1: ≥12 to <18 years TOL/TAZ 1000/500 mg FDC

Ceftolozane/Tazobactam 30/15 mg/kg DRUG

A FDC of 30 mg/kg of ceftolozane and 15 mg/kg of tazobactam as a 60 minute infusion.

Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg; Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg

Ceftolozane/Tazobactam 20/10 mg/kg DRUG

A FDC of 20 mg/kg of ceftolozane and 10 mg/kg of tazobactam as a 60 minute infusion.

Cohort 5: birth to <3 months TOL/TAZ 20/10 mg/kg; Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg

Ceftolozane/Tazobactam 18/9 mg/kg DRUG

A FDC of 18 mg/kg of ceftolozane and 9 mg/kg of tazobactam as a 60 minute infusion.

Cohort 2: ≥7 to <12 years TOL/TAZ 18/9 mg/kg; Cohort 3: ≥2 to <7 years TOL/TAZ 18/9 or 30/15 mg/kg; Cohort 4: ≥3 months to <2 years TOL/TAZ 18/9 or 30/15 mg/kg

Ceftolozane/Tazobactam 12/6 mg/kg DRUG

A FDC of 12 mg/kg of ceftolozane and 6 mg/kg of tazobactam as a 60 minute infusion.

Cohort 6: birth to <3 months TOL/TAZ 12/6 or 20/10 mg/kg

Eligibility Criteria

• Age: 7 Days - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Related Publications (1)

• 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.

  PMID: 30153232 DERIVED

MeSH Terms

Interventions

ceftolozane; Tazobactam

Intervention Hierarchy (Ancestors)

Penicillanic Acid; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Sulfones; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 22, 2014
• First Posted: October 17, 2014
• Study Start: September 17, 2014
• Primary Completion: June 8, 2017
• Study Completion: June 15, 2017
• Last Updated: September 11, 2019
• Results First Posted: February 15, 2019

Record last verified: 2019-08

Data Sharing

• IPD Sharing: Will share