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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CAZ-AVI or CXL | Experimental | 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) |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CAZ-AVI | Drug | IV infusion |
|
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| Measure | Description | Time Frame |
|---|---|---|
| Changes in the intestinal flora of healthy subjects after administration of ceftazidime-avibactam (CAZ-AVI) and ceftaroline fosamil -avibactam (CXL). | The number and types of microorganisms in faeces. | Change from baseline (Day-1) at Day 2, 5, 7, 10, 14 and 21 |
| Measure | Description | Time Frame |
|---|---|---|
| Safety and tolerability | Adverse event, ECG, safety laboratory assessments, physical examinations and vital signs. | Screening up to 12 days after discharge from study site |
| Pharmacokinetics of CAZ-AVI in healthy volunteers |
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Inclusion Criteria:
Provision of signed and dated, written informed consent prior to any study specific procedures
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:
Have a body mass index (BMI) between 19 and 30 kg/m2.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Paul Newell, MD | AstraZeneca R&D, Alderly Park, Mereside, SK 104TG, Macclesfield, Cheshire, United Kingdom | Study Director |
| Sandhia Ponnarambil, MD | AstraZeneca R&D Alderly Park, Parklands, SK 104TF, Macclesfield, Cheshire, United Kingdom | Study Chair |
| Georgios Panagiotidis, MD | Clinical Pharmacology Trial Unit, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Research Site | Stockholm | Sweden |
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| CXL |
| Drug |
IV infusion |
|
|
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).
| 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) |
| Pharmacokinetics of CXL in healthy volunteers | 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). | 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) |
| To measure CAZ-AVI and CXL plasma and faecal concentrations using bioactivity techniques. | The concentrations of CAZ-AVI and CXL will be determined in plasma and faecal samples. | Day -1, 2, 5, 7, 10, 14 and 21 |
| 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. | Minimal inhibitory concentration (MIC) for CAZ-AVI and CXL will be determined for new colonizing bacteria from faecal samples. | Day -1, 2, 5, 7, 10, 14 and 21 |
| ID | Term |
|---|---|
| C423142 | KPNA1 protein, human |
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