Pharmacokinetic Study of Ceftaroline Fosamil/Avibactam in Adults With Augmented Renal Clearance

A Phase 1, Multicenter, Open-label, Single-dose Study to Assess the Pharmacokinetics of Ceftaroline Fosamil/Avibactam in Adults With Augmented Renal Clearance

To evaluate the pharmacokinetic (PK) profiles of ceftaroline and avibactam in adults with augmented renal clearance (ARC).

Study Overview

• Status: Completed
• Conditions: Systemic Inflammatory Response Syndrome (SIRS); Augmented Renal Clearance (ARC)
• Intervention / Treatment: Drug: Ceftaroline fosamil/Avibactam (CXL)

Detailed Description

To evaluate the single-dose pharmacokinetic (PK) profiles of ceftaroline and avibactam following intravenous (IV) administration of ceftaroline fosamil/avibactam ("CXL") in adults with augmented renal clearance (ARC).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Investigational Site
    • Southport, Queensland, Australia, 4215
      • Investigational Site
• United States
  • California
    • Fresno, California, United States, 93711
      • Investigational Site
    • Los Angeles, California, United States, 90033
      • Investigational Site
    • San Diego, California, United States, 92123
      • Investigational Site
    • Stanford, California, United States, 94605
      • Investigational Site
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Investigational Site
  • Florida
    • Gainesville, Florida, United States, 32610
      • Investigational Site
    • Miami, Florida, United States, 33136
      • Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Investigational Site
    • Maywood, Illinois, United States, 60153
      • Investigational Site
    • Peoria, Illinois, United States, 61606
      • Investigational Site
  • Minnesota
    • Duluth, Minnesota, United States, 55805
      • Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68131
      • Investigational Site
  • New Jersey
    • Neptune, New Jersey, United States, 07753
      • Investigational Site
  • North Carolina
    • Winston Salem, North Carolina, United States, 27157
      • Investigational Site
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Investigational Site
    • Columbus, Ohio, United States, 43210
      • Investigational Site
    • Dayton, Ohio, United States, 45409
      • Investigational Site
  • Texas
    • Houston, Texas, United States, 77401
      • Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female adults ≥ 18 and ≤ 55 years old

• Augmented renal clearance, defined as:

  • Estimated CrCl ≥ 115 mL/min (calculated using modified Cockcroft-Gault, before the measured 8-hour urine collection)
  • Measured CrCl ≥ 140 mL/min (from an 8-hour urine collection)

• Hospitalized and diagnosed with SIRS, defined by at least 2 of the following:

  • Temperature (oral, rectal, tympanic, or core) > 38.5°C or < 35.0°C
  • Heart rate > 90 beats/min
  • Respiratory rate > 20 breaths/min or PaCO2 < 32 mmHg
  • Leukocytosis (> 12,000 white blood cells [WBC]/mm3), leukopenia (< 4000 WBC/mm3), or bandemia (> 10% immature neutrophils [bands] regardless of total peripheral WBC)
• Requires indwelling urinary bladder catheter per standard of care (through the end of the 8-hour urine collection)

Exclusion Criteria:

• History of any known hypersensitivity or allergic reaction to cephalosporins or any β-lactam antimicrobial (eg, penicillins)
• History of chronic kidney disease, hemodialysis, or peritoneal dialysis; or history of acute renal replacement therapy (eg, hemodialysis, hemofiltration) associated with current illness
• Suspected rhabdomyolysis or creatine kinase > 10,000 U/L
• Significant anemia defined as hemoglobin < 9 g/dL or hematocrit < 27%
• Transfusion of packed red blood cells (PRBC) or whole blood within 24 hours of study drug infusion or anticipated need for a transfusion before the last PK blood sample is collected
• If female, currently pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ceftaroline fosamil/Avibactam	Drug: Ceftaroline fosamil/Avibactam (CXL); IV infusion of CXL (combination of ceftaroline fosamil [600 mg] plus avibactam [600 mg]) infused over 60 (± 5) minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Pharmacokinetic Parameters of Ceftaroline and Avibactam: Area under the plasma concentration versus time curve, Cmax, Tmax, T½, , CL, Vz, and Vss.	The following PK parameters, if calculable, will be determined for ceftaroline, ceftaroline fosamil, ceftaroline M-1, and avibactam: area under the plasma concentration versus time curve, Cmax, time of maximum plasma drug concentration (Tmax), T½, apparent total body clearance of drug from plasma (CL), apparent volume of distribution during the terminal phase (Vz), and Vss.	Up to 3 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of a Single Dose of IV Ceftaroline fosamil and Avibactam.	Adverse events will be summarized. Vital signs (pulse, blood pressure, respiratory rate, temperature), oxygen saturation and concomitant medications will be summarized. Complete blood count (CBC) and comprehensive metabolic panel results will be summarized.	24-36 hours after last study procedure

Collaborators and Investigators

• Sponsor: Forest Laboratories

Publications and helpful links

General Publications

• Li J, Lovern M, Green ML, Chiu J, Zhou D, Comisar C, Xiong Y, Hing J, MacPherson M, Wright JG, Riccobene T, Carrothers TJ, Das S. Ceftazidime-Avibactam Population Pharmacokinetic Modeling and Pharmacodynamic Target Attainment Across Adult Indications and Patient Subgroups. Clin Transl Sci. 2019 Mar;12(2):151-163. doi: 10.1111/cts.12585. Epub 2018 Sep 28.

Study record dates

Study Major Dates

• Study Start: May 1, 2012
• Primary Completion (Actual): March 1, 2013
• Study Completion (Actual): March 1, 2013

Study Registration Dates

• First Submitted: June 14, 2012
• First Submitted That Met QC Criteria: June 18, 2012
• First Posted (Estimate): June 20, 2012

Study Record Updates

• Last Update Posted (Actual): April 7, 2017
• Last Update Submitted That Met QC Criteria: April 6, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation; Shock; Systemic Inflammatory Response Syndrome; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Ceftaroline fosamil; Avibactam
• Other Study ID Numbers: CXL-PK-04