A Study to Investigate the Effect of Administration of Ceftazidime-avibactam (CAZ-AVI) and Ceftaroline Fosamil -Avibactam (CXL) on the Intestinal Flora of Healthy Volunteers

Phase 1

Completed

• Conditions: Pharmacokinetics; Open Label; CXL; Effect on Intestinal Flora; CAZ-AVI; Safety
• Interventions: Drug: CAZ-AVI; Drug: CXL

• Registration Number: NCT01789528
• Lead Sponsor: Pfizer

Brief Summary

The purpose of this study is to investigate the effect of administration of CAZ-AVI and CXL on the intestinal flora of male and female healthy volunteers after multiple administrations over 7 days. An assessment of the effect on intestinal flora is an important aspect to understand for the safe clinical use of the investigational products and is expected by regulatory agencies.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2013-02-04
• Study First Submitted QC: 2013-02-11
• Study First Posted: 2013-02-12
• Study Start: 2013-08
• Primary Completion: 2014-03
• Study Completion: 2014-03
• Status Verified: 2017-09
• Last Update Submitted: 2017-09-01
• Last Update Posted: 2017-09-05

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

1. Provision of signed and dated, written informed consent prior to any study specific procedures

2. Healthy male and female volunteers aged 18 to 45 years (inclusive) with suitable veins for cannulation or repeated venepuncture.

   Females: Female healthy volunteers are authorised to participate in this study if both of the following criteria are met:

   1. A negative serum pregnancy test BOTH at screening AND at admission to the study centre.
   2. Agrees not to attempt pregnancy while receiving investigational product and for a period of 7 days after last investigational product administration, and agrees to the use of acceptable methods of contraception (according to instructions) prior to, during, and for 7 days after the last investigational product administration.

3. Have a body mass index (BMI) between 19 and 30 kg/m2.

Exclusion Criteria

1. History or presence of gastrointestinal, hepatic, or renal disease or any other condition known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
2. Any clinically significant abnormalities in physical examination, ECG, clinical chemistry, haematology, coagulation, or urinalysis results, as judged by the investigator.
3. Pregnant or breastfeeding female healthy volunteers.
4. History of any clinically significant disease or disorder which, in the opinion of the investigator, may either put the healthy volunteer at risk because of participation in the study, or influence the results or the healthy volunteer's ability to participate in the study.
5. Known history of Clostridium difficile infection in last 3 months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CAZ-AVI or CXL	CAZ-AVI	Cohort 1: CAZ-AVI (2000 mg ceftazidime and 500 mg avibactam) by intravenous infusion given over 2 hours, every 8 hours Cohort 2: CXL (600 mg ceftaroline fosamil and 600 mg avibactam)
CAZ-AVI or CXL	CXL	Cohort 1: CAZ-AVI (2000 mg ceftazidime and 500 mg avibactam) by intravenous infusion given over 2 hours, every 8 hours Cohort 2: CXL (600 mg ceftaroline fosamil and 600 mg avibactam)

Primary Outcome Measures

Name	Time	Method
Changes in the intestinal flora of healthy subjects after administration of ceftazidime-avibactam (CAZ-AVI) and ceftaroline fosamil -avibactam (CXL).	Change from baseline (Day-1) at Day 2, 5, 7, 10, 14 and 21	The number and types of microorganisms in faeces.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics of CAZ-AVI in healthy volunteers	Days 1, 2 and 5: Pre-dose and 2 hours post dose. Day 7: pre-dose, 0.5, 1, 1.5, 2, 2.25, 2.5, 2.75, 3, 3.5, 4, 6, 8, 12, and 24 hours post dose (Day 8)	On Day 7, the following pharmacokinetic parameters will be calculated when applicable: Maximum plasma concentration (Cmax), time of Cmax (tmax), time of last quantifiable plasma concentration (last), area under the plasma concentration-time curve during the dosing interval (AUC(0-τ)), area under the plasma concentration time curve from zero to the time of the last quantifiable concentration (AUC(0-t)), half-life (t½), systemic plasma clearance (CL), apparent plasma clearance (CL/F), volume of distribution at steady state (Vss), and apparent volume of distribution (Vz/F).
Safety and tolerability	Screening up to 12 days after discharge from study site	Adverse event, ECG, safety laboratory assessments, physical examinations and vital signs.
To measure CAZ-AVI and CXL plasma and faecal concentrations using bioactivity techniques.	Day -1, 2, 5, 7, 10, 14 and 21	The concentrations of CAZ-AVI and CXL will be determined in plasma and faecal samples.
To describe the in vitro susceptibility of new colonizing bacteria of the intestinal microflora to CAZ-AVI and CXL during and after CAZ-AVI and CXL administration.	Day -1, 2, 5, 7, 10, 14 and 21	Minimal inhibitory concentration (MIC) for CAZ-AVI and CXL will be determined for new colonizing bacteria from faecal samples.
Pharmacokinetics of CXL in healthy volunteers	Days 1, 2 and 5: Pre-dose and 1 hour post dose. Day 7: pre-dose, 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 5, 7, 8, 12, and 24 hours post dose (Day 8)	On Day 7, the following pharmacokinetic parameters will be calculated when applicable: Maximum plasma concentration (Cmax), time of Cmax (tmax), time of last quantifiable plasma concentration (last), area under the plasma concentration-time curve during the dosing interval (AUC(0-τ)), area under the plasma concentration time curve from zero to the time of the last quantifiable concentration (AUC(0-t)), half-life (t½), systemic plasma clearance (CL), apparent plasma clearance (CL/F), volume of distribution at steady state (Vss), and apparent volume of distribution (Vz/F).

Trial Locations

Locations (1)

Research Site; 🇸🇪 Stockholm, Sweden