Study to Assess the Concentration of Avibactam and Ceftazidime in Epithelial Lining Fluid and Plasma

A Phase I Open-Label, 2-Part, 3-Cohort, Single-Centre Study to Assess the Concentration of Avibactam and Ceftazidime in Epithelial Lining Fluid (ELF) and Plasma Using at Least Two Different Dosing Regimens in Healthy Volunteers

This is an open-label study divided in 2 parts and 3 cohorts to determine the concentration of Avibactam and Ceftazidime in the lining of the lungs and the blood.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: CAZ104

Detailed Description

A Phase I Open-Label, 2-Part, 3-Cohort, Single-Centre Study to Assess the Concentration of Avibactam and Ceftazidime in Epithelial Lining Fluid and Plasma Using at Least Two Different Dosing Regimens in Healthy Volunteers

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Provision of signed and dated, written informed consent prior to any study specific procedures
• Healthy male and female subjects 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 admission to the unit, must not be lactating and must be of non-child-bearing potential
• Male subjects should be willing to use barrier contraception ie, condoms, from dosing to 3 months after dosing with the IP
• 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 or presence of any clinically significant disease or disorder (including a history of chronic respiratory disease eg, asthma, chronic obstructive pulmonary disease [COPD], cystic fibrosis or interstitial lung disease) 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
• Known allergy to lidocaine/lignocaine, midazolam, alfentanyl or other topical anaesthetics/sedatives in similar classes to these agents
• Any clinically significant illness, medical/surgical procedure or trauma within 4 weeks of the first administration of IP
• Any clinically significant abnormalities in physical examination, lung function test, ECG, clinical chemistry, haematology, coagulation screen, or urinalysis results as judged by the Investigator

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; CAZ104 (2000mg Ceftazidime/500mg Avibactam)	Drug: CAZ104; IV Infusion; Other Names: CAZ104 (3000mg Ceftazidime/1000mg Avibactam)
Experimental: 2; CAZ104 (3000mg Ceftazidime/1000mg Avibactam)	Drug: CAZ104; IV Infusion; Other Names: CAZ104 (3000mg Ceftazidime/1000mg Avibactam)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To measure and compare the concentration of Avibactam and Ceftazidime in ELF and plasma	To measure and compare the concentration of Avibactam and Ceftazidime in ELF and plasma by assessment of maximum concentration (Cmax), time to Cmax (tmax), area under the concentration time curve during a dosing interval t (AUCτ), terminal half life (t½λz) in plasma and ELF, plasma clearance (CL), volume of distribution at steady state (Vss) and at the terminal phase (Vz) in plasma, ratio of Cmax in ELF over Cmax in plasma and ratio of AUCτ in ELF over AUCτ in plasma.	at several timepoints from pre-dose up to 5 days post dose (Part 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate safety and tolerability of Avibactam and Ceftazidime	To evaluate safety and tolerability of Avibactam and Ceftazidime by assessment of adverse events (AEs), physical examinations, vital signs, 12 lead electrocardiograms (ECGs), Pulse oximetry and safety laboratory assessments	at several timepoints from pre-dose up to 5 days post dose

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Principal Investigator: Leonard Siew, MBCHB, MRCP(UK), Quintiles Phase I unit London; Study Chair: Mirjana Kujacic, MD, AstraZeneca

Publications and helpful links

General Publications

• Nicolau DP, Siew L, Armstrong J, Li J, Edeki T, Learoyd M, Das S. Phase 1 study assessing the steady-state concentration of ceftazidime and avibactam in plasma and epithelial lining fluid following two dosing regimens. J Antimicrob Chemother. 2015 Oct;70(10):2862-9. doi: 10.1093/jac/dkv170. Epub 2015 Jul 1.

Helpful Links

• Clinical Study Protocol

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: July 14, 2011
• First Submitted That Met QC Criteria: July 14, 2011
• First Posted (Estimate): July 15, 2011

Study Record Updates

• Last Update Posted (Actual): September 1, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Phase 1; open label; healthy male and female (post menopausal) volunteers; CAZ104; Avibactam; Ceftazidime; open label, at least 2 different regimens, concentration of investigational product (IP), CAZ104, Avibactam, Ceftazidime, Cmax, tmax
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; beta-Lactamase Inhibitors; Avibactam; Ceftazidime
• Other Study ID Numbers: D4280C00009