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Antibiotic Distribution and Recovery in Tissue

Periodic Reporting for period 2 - AB-DiRecT (Antibiotic Distribution and Recovery in Tissue)

Reporting period: 2020-07-01 to 2021-08-31

Gepotidacin is a novel antibiotic currently in Phase 3 development by GlaxoSmithKline Pharmaceuticals (GSK) as a potential treatment for uncomplicated urinary tract infection and uncomplicated gonorrhea. The distribution of this antibiotic in peripheral tissues after systemic administration (distribution of the drug throughout the body) is not known.
The aim of this project is to investigate the potential of a new antibiotic for the treatment of a bacterial infection of the throat (pharyngeal gonorrhea) caused by the bacteria Neisseria gonorrhoeae or prostatitis (inflammation of the prostate) caused by the bacteria Escherichia coli, by demonstrating sufficient penetration of this novel antibiotic into tonsils and prostate tissue. The work planned includes in vitro experiments (in a test tube or similar), animal experiments, and a Phase 1 clinical study in healthy human volunteers.
The objective of the Phase 1 clinical study is to measure the level of gepotidacin in prostate and tonsil tissue. The measurement of the drug level will be performed, after a single oral dose of gepotidacin, in the tissue which has been removed within the surgery. For this purpose, a method called microdialysis will be used. Microdialysis is an established technique used to directly measure free drug concentrations in the space between cells, including soft tissues. If there is enough healthy tissue an additional small part will be frozen and subsequently used for a further established method to determine the concentration of drug. The methods used in this clinical study are exclusively ex vivo (outside a living organism) in tonsil and prostate tissue.
AB-Direct planned to conduct experiments in a rat model of prostatitis to predict human exposures of gepotidacin in healthy and infected prostate. These experiments are ongoing.
A bioanalytical method for gepotidacin quantitation was successfully established and validated. Furthermore, these in vitro studies to enable the planned clinical study, demonstrated that microdialysis with gepotidacin is feasible and provides reliable results.
Most importantly, a Phase 1 human clinical study, to investigate tissue distribution of the novel antibiotic gepotidacin, has been launched at the beginning of February 2021 at the Department of Clinical Pharmacology, Medical University of Vienna, with Inserm as study Sponsor. This study involves an ex-vivo microdialysis procedure post-surgery. The first subjects for tonsillectomy and prostatectomy have been enrolled.

AB-Direct has made considerable progress in developing mathematical models that relate the gepotidacin tissue exposure with the effect, from data that describes the killing activity of the antibiotic on the relevant bacteria in vitro. Two models have been built to describe the data for the bacteria Escherichia coli and the bacteria Neisseria gonorrhoeae. These models are able to describe the effects of gepotidacin over time in vitro. The models have several limitations, but we believe they can play a valuable role in estimation of the dosage regimens needed to eradicate E. coli and N. gonorrhoeae and avoid the emergence of resistance. Animal model and clinical data will also be critical components of dose selection.
The major expected impacts of the AB-Direct project are as follows:
- Enhancing the pipeline of treatment options for bacterial infections of the tonsil or prostate by determination of the tissue penetration characteristics of a novel mechanism of action antibiotic;
- Continuing the history of EU-based public-private partnership clinical research to deliver new knowledge and treatment options for antimicrobial resistant infections;
- Contributing to the scientific understanding of the translational aspects across species and of the use of tissue distributions to refine anti-infective dosing recommendations;
- Thereby developing scientifically and regulatory sound pathways that will allow for more efficient development of novel antibiotics in the future.
The progress we have made regarding these potential impacts is described above and includes building preliminary mathematical models that relate tissue exposure with the effect of the drug, and starting the clinical study in human volunteers which forms the central part of this project. Results expected at the end of the project (data from the animal model, refinement and use of the mathematical models, data from the clinical trial) will allow us to realize some or all of these impacts.
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