Dose-exposure-response relationships for ceftazidime-avibactam of value to explore dose individualization strategies

Lead Investigator: Lena Friberg, Uppsala University
Title of Proposal Research: Dose-exposure-response relationships for ceftazidime-avibactam of value to explore dose individualization strategies
Vivli Data Request: 9090
Funding Source: (1) TIPAT (Marie Curie Innovative Training Network): European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No 861323. (2) Swedish Research Council, grant No 2022-00657.
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Antimicrobial resistance is a pressing global concern rendering traditional treatments ineffective. Ceftazidime, a vital β-lactam antibiotic, faces such challenges, with bacterial strains producing enzymes known as β-lactamases that critically reduce its effectiveness. To counter this, ceftazidime is paired with avibactam, a β-lactamase inhibitor, forming the combination ceftazidime-avibactam (CAZ-AVI). This combination, approved for severe infections involving multidrug-resistant bacteria, presents a crucial solution for conditions like complicated intra-abdominal infection, complicated urinary tract infection, and pneumonia.

The importance of our research lies in understanding the dose-exposure (i.e. pharmacokinetics) and exposure-response (i.e. pharmacodynamics) relationships for CAZ-AVI to explore personalized dosing strategies. Antibiotic resistance demands innovative approaches, and our research aims to impact medical science by contributing evidence for optimizing CAZ-AVI treatment. To conduct this research, we’ll use pharmacometrics, a science quantifying drug, disease and clinical trial information to aid efficient drug development. Our focus is on exploring correlations between the pharmacokinetic parameters of ceftazidime and avibactam at the individual level. By developing a joint population pharmacokinetic model, we aim to guide therapeutic drug monitoring, offering insights into whether monitoring both compounds is necessary for optimal dosing.

Our investigation extends to pharmacometric multistate models, exploring time-dependent variables and exposure metrics to predict treatment outcomes. This multistate analysis will consider clinical, microbiological, and safety-related outcomes. Understanding these factors can unveil the intricate dose-exposure-response relationship for CAZ-AVI, aiding in defining exposure targets. By exploring these aspects, we aim to pave the way for personalized treatment strategies, ensuring the effectiveness of CAZ-AVI in eradicating infections while minimizing adverse effects.

In summary, our research on dose-exposure-response relationships for CAZ-AVI is a crucial step toward personalized antibiotic treatment, contributing to fight antimicrobial resistance. Through pharmacometrics and multistate modeling, we hope to better understand how different factors may impact the outcome and clarify the dose-exposure-response for CAZ-AVI, with the ultimate goal to define exposure targets, and integrate important patient factors, to optimally personalize CAZ-AVI treatment to fit the needs of each patient.

Requested Studies:

A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, DOUBLE-DUMMY, PARALLEL-GROUP, COMPARATIVE STUDY TO DETERMINE THE EFFICACY, SAFETY, AND TOLERABILITY OF CEFTAZIDIME-AVIBACTAM (CAZ-AVI) PLUS METRONIDAZOLE VERSUS MEROPENEM IN THE TREATMENT OF COMPLICATED INTRA-ABDOMINAL INFECTIONS (CIAIS) IN HOSPITALIZED ADULTS
Data Contributor: Pfizer Inc.
Study ID: NCT01499290
Sponsor ID: NCT01499290

Compare Ceftazidime-Avibactam + Metronidazole vs Meropenem for hospitalized adults with complicated Intra-Abd Infections
Data Contributor: Pfizer Inc.
Study ID: NCT01726023
Sponsor ID: NCT01726023

Ceftazidime-Avibactam for the treatment of infections due to Ceftazidime Resistant Pathogens
Data Contributor: Pfizer Inc.
Study ID: NCT01644643
Sponsor ID: NCT01644643

A PHASE III, RANDOMIZED, MULTICENTER, DOUBLE-BLIND, DOUBLE DUMMY, PARALLEL GROUP, COMPARATIVE STUDY TO DETERMINE THE EFFICACY, SAFETY, AND TOLERABILITY OF CEFTAZIDIME-AVIBACTAM (CAZ-AVI, FORMERLY CAZ104) VERSUS DORIPENEM FOLLOWED BY APPROPRIATE ORAL THERAPY IN THE TREATMENT OF COMPLICATED URINARY TRACT INFECTIONS, INCLUDING ACUTE PYELONEPHRITIS, WITH A GRAM NEGATIVE PATHOGEN IN HOSPITALIZED ADULTS
Data Contributor: Pfizer Inc.
Study ID: NCT01595438
Sponsor ID: NCT01595438

A Phase III, Randomized, Multicenter, Double-Blind, Double Dummy, Parallel Group, Comparative Study to Determine the Efficacy, Safety, and Tolerability of Ceftazidime Avibactam (CAZ-AVI, Formerly CAZ104) Versus Doripenem Followed by Appropriate Oral Therapy in the Treatment of Complicated Urinary Tract Infections, Including Acute Pyelonephritis, With a Gram Negative Pathogen in Hospitalized Adults
Data Contributor: Pfizer Inc.
Study ID: NCT01599806
Sponsor ID: NCT01599806

Comparative Study of NXL104/ceftazidime versus comparator in adults with complicated urinary tract infections
Data Contributor: Pfizer Inc.
Study ID: NCT00690378
Sponsor ID: NCT00690378

A PROSPECTIVE, MULTICENTER, DOUBLE-BLIND, RANDOMIZED, COMPARATIVE STUDY TO ESTIMATE THE SAFETY, TOLERABILITY AND EFFICACY OF NXL104/CEFTAZIDIME PLUS METRONIDAZOLE VS. MEROPENEM IN THE TREATMENT OF COMPLICATED INTRA-ABDOMINAL INFECTIONS IN HOSPITALIZED ADULTS
Data Contributor: Pfizer Inc.
Study ID: NCT00752219
Sponsor ID: NCT00752219

A Phase III, Randomized, Multicentre, Double-blind, Double-dummy, Parallel-group Comparative Study to Determine the Efficacy, Safety And Tolerability of Ceftazidime-Avibactam Versus Meropenem in the Treatment of Nosocomial Pneumonia Including Ventilator-Associated Pneumonia in Hospitalized Adults
Data Contributor: Pfizer Inc.
Study ID: NCT01808092
Sponsor ID: NCT01808092