A Study to Assess the Levels of Two Antibiotics in the Blood When Given Together and Separately

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01430910
First received: September 7, 2011
Last updated: October 19, 2012
Last verified: October 2012
  Purpose

This is a randomised study divided into 2 parts. Part A investigates the effect of prolonged dosing (ten days) with Avibactam and Ceftazidime when given together and how this will effect how much Avibactam and Ceftazidime enters the blood. Part B investigates how much Avibactam (NXL104) and Ceftazidime enter the blood when Avibactam and Ceftazidine are given separately or together intravenously.


Condition Intervention Phase
Healthy
Drug: CAZ104
Drug: Avibactam
Drug: Ceftazidime
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Basic Science
Official Title: A Phase I, 2-Part, Open-Label, Pharmacokinetic and Drug-Drug Interaction Study of CAZ104 (Avibactam and Ceftazidime in Healthy Subjects)

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including maximum plasma concentration (Cmax) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including time of Cmax (tmax) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including minimum plasma concentration (Cmin) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including time of Cmin (tmin) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including last quantifiable plasma concentration (Clast) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including time of Clast (tlast) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including average plasma concentration during a dosing interval (Cavg) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including fluctuation index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including area under the curve of plasma drug concentration (AUC) - time curve from zero to the time of the last quantifiable concentration [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including AUC, Day 1 only [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including AUC during the dosing interval [AUC(0-τ)] [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including terminal half-life (t1/2) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including systemic plasma clearance (CL) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including volume of distribution at steady state (Vss) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including volume of distribution at the terminal phase (Vz) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including accumulation ratio for Cmax and AUC(0-τ) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Plasma pharmacokinetic variables will be measured including linearity index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Urine pharmacokinetic variables will be measured including amount of drug excreted unchanged into urine from zero to time t [Ae(0-t)] [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Urine pharmacokinetic variables will be measured including fraction of dose excreted unchanged into urine (fe; % dose) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Avibactam. Urine pharmacokinetic variables will be measured including renal clearance (CLR) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Cmax [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including tmax [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Cmin [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including tmin [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Clast [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including tlast [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Cavg [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including fluctuation index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including AUC(0-t) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including AUC, Day 1 only [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including AUC(0-τ) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including t1/2 [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including CL [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Vss [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including Vz [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including accumulation ratio for Cmax and AUC(0-τ) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Plasma pharmacokinetic variables will be measured including linearity index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Urine pharmacokinetic variables will be measured including Ae(0-t) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Urine pharmacokinetic variables will be measured including fe; % dose [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part A: Single- and multiple-dose pharmacokinetics of Ceftazidime. Urine pharmacokinetic variables will be measured including CLR [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Cmax [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including tmax [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Cmin [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including tmin [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Clast [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including tlast [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Cavg [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including fluctuation index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including AUC(0-t) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including AUC, Day 1 only [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including AUC(0-τ) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including t1/2 [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including CL [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Vss [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including Vz [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including accumulation ratio for Cmax and AUC(0-τ) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Plasma pharmacokinetic variables will be measured including linearity index [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Urine pharmacokinetic variables will be measured including Ae(0-t) [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Urine pharmacokinetic variables will be measured including fe; % dose [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]
  • Part B: Pharmacokinetics of co-administering Avibactam plus Ceftazidime (CAZ104) compared to administration of the individual components. Urine pharmacokinetic variables will be measured including CLR [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess safety and tolerability of Avibactam by assessment of Adverse events [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Avibactam by clinical laboratory assessments [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Avibactam by assessment of vital signs [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Avibactam by assessment of safety electrocardiogram [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Avibactam by assessment of physical examination [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Avibactam by assessment of withdrawn [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by assessment of Adverse events [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by clinical laboratory assessments [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by assessment of vital signs [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by assessment of safety electrocardiogram [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by assessment of physical examination [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of Ceftazidime by assessment of withdrawn [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by assessment of Adverse events [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by clinical laboratory assessments [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by assessment of vital signs [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by assessment of safety electrocardiogram [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by assessment of physical examination [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]
  • To assess safety and tolerability of CAZ104 by assessment of withdrawn [ Time Frame: Up to 24 hours post last dose ] [ Designated as safety issue: Yes ]

Enrollment: 43
Study Start Date: September 2011
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
CAZ104 (2000mg Ceftazidime/500mg Avibactam)
Drug: CAZ104
IV infusion
Active Comparator: 2
500mg Avibactam
Drug: Avibactam
IV infusion
Active Comparator: 3
2000mg Ceftazidime
Drug: Ceftazidime
IV infusion

Detailed Description:

A Phase I, 2-Part, Open-Label, Pharmacokinetic and Drug-Drug Interaction Study of CAZ104 (Avibactam and Ceftazidime in Healthy Subjects)

  Eligibility

Ages Eligible for Study:   18 Years to 50 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Provision of signed and dated, written informed consent prior to any study specific procedures
  • Healthy male and female subjects aged 18 to 50 years with veins suitable for cannulation or repeated venepuncture; female subjects must be postmenopausal or surgically sterile. Female subjects must have a negative pregnancy test at screening and on admi
  • Male subjects should be willing to use barrier contraception ie, condoms, from dosing to 3 months after dosing with the IP (investigational product).
  • Have a body mass index (BMI) between 19 and 30 kg/m2
  • As judged by the Investigator, all the subjects must be able to understand and be willing to comply with study procedures, restrictions and requirements

Exclusion Criteria:

  • History of any clinically significant disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study, or influence the results or the subject's ability to participate in the study
  • History or presence of gastrointestinal, hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs
  • History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to drugs with a similar chemical structure or class to avibactam, ceftazidime, and/or excipients
  • Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IP Prolonged QTcF (>450 ms) or shortened QTcF (<350 ms) or a family history of long QT syndrome
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01430910

Locations
United Kingdom
Research site
London, United Kingdom
Sponsors and Collaborators
AstraZeneca
Investigators
Study Chair: Mirjana Kujacic, MD AstraZeneca Research and DevelopmentSE-431 83 Mölndal Sweden
Principal Investigator: Leonard Siew, MBCHB Quintiles Drug Research Unit at Guy's Hospital 6 Newcomen St London SE1 1YR United Kingdom
Study Director: Paul Newell, MD AstraZeneca R&D Alderly Park, Mereside SK 104 TG Macclesfield, Cheshire United Kingdom
  More Information

No publications provided

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01430910     History of Changes
Other Study ID Numbers: D4280C00011
Study First Received: September 7, 2011
Last Updated: October 19, 2012
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by AstraZeneca:
Phase 1
open label
ceftazidime
pharmacokinetics
urinary tract infection
intra-abdominal infection

Additional relevant MeSH terms:
Ceftazidime
Anti-Bacterial Agents
Anti-Infective Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014