Periodic Reporting for period 4 - AB-DiRecT (Antibiotic Distribution and Recovery in Tissue)
Período documentado: 2022-10-01 hasta 2023-09-30
Gepotidacin is a novel antibiotic currently in Phase 3 development by GSK as a potential treatment for uncomplicated urinary tract infection and uncomplicated gonorrhea. Before this project, the distribution of this antibiotic at infection site in peripheral tissues after oral administration (distribution of the drug throughout the body) was not well understood.
The aim of this project was to investigate the potential of this 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 and now completed includes in vitro experiments (in a test tube or similar), animal experiments, and a Phase 1 clinical study in patients undergoing prostate surgery or tonsillectomy.
The objective of the Phase 1 clinical study was to measure the concentrations of gepotidacin in prostate and tonsil tissue. The measurement of the drug was 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 was used. Microdialysis consists of placing an artificial capillary in a tissue to directly measure drug concentrations in the space between cells, including soft tissues, where the bacteria establish an infection.
The aim of this project was to investigate the potential of this 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 and now completed includes in vitro experiments (in a test tube or similar), animal experiments, and a Phase 1 clinical study in patients undergoing prostate surgery or tonsillectomy.
The objective of the Phase 1 clinical study was to measure the concentrations of gepotidacin in prostate and tonsil tissue. The measurement of the drug was 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 was used. Microdialysis consists of placing an artificial capillary in a tissue to directly measure drug concentrations in the space between cells, including soft tissues, where the bacteria establish an infection.
AB-DIRECT has completed the three different arms of this project.
At the University of Poitiers, a rat model of prostatitis was developed and in vivo (inside a living organism) microdialysis experiments were conducted to understand the distribution of gepotidacin in prostate tissue in that model. These animal studies were necessary as this was the only way to determine concentrations at multiple time points and to assess the effect of infection on tissue distribution. In-vivo microdialysis cannot be performed in human prostate. Data from these studies confirmed that gepotidacin is distributed to prostate tissue after animals receive a dose and provided information on how the concentration in prostate changes over time and with infection status.
The Phase 1 human clinical study, to investigate tissue distribution of gepotidacin was initiated at the beginning of February 2021 at the Department of Clinical Pharmacology, Medical University of Vienna, with INSERM as study Sponsor. Subjects were also enrolled at the Department of Urology, University Hospital of Tours and at Clinik Donaustadt in Vienna. This study involves an ex vivo (outside a living organism) microdialysis procedure to measure the concentration of gepotidacin in tissues removed during surgery. The study completed enrollment in May 2023 with a total of 48 subjects enrolled and receiving a single dose of gepotidacin. Data from this study indicated that gepotidacin is distributed to prostate and tonsil tissue after an oral dose and provided information on how the concentration in these tissues changes over time.
At the University of Poitiers, using the data from both animal model and clinical studies, we have developed models that enable us to predict tissue exposure in humans after various doses and relate that to the effect of the drug. These models allow us to extrapolate between species so that we can translate future animal model data to expand our knowledge beyond the human study that is limited to a single time point per individual. These models will be a critical tool for future gepotidacin dose selection when considering infections where tissue distribution is likely to play an important role in efficacy, for example in infections of the throat or prostate.
These valuable scientific data were generated as a result of the diversity of thought and experience and the excellent collaboration between the partners in this IMI project. The success of this project highlights the importance of public-private partnerships to deliver innovative science in this area.
At the University of Poitiers, a rat model of prostatitis was developed and in vivo (inside a living organism) microdialysis experiments were conducted to understand the distribution of gepotidacin in prostate tissue in that model. These animal studies were necessary as this was the only way to determine concentrations at multiple time points and to assess the effect of infection on tissue distribution. In-vivo microdialysis cannot be performed in human prostate. Data from these studies confirmed that gepotidacin is distributed to prostate tissue after animals receive a dose and provided information on how the concentration in prostate changes over time and with infection status.
The Phase 1 human clinical study, to investigate tissue distribution of gepotidacin was initiated at the beginning of February 2021 at the Department of Clinical Pharmacology, Medical University of Vienna, with INSERM as study Sponsor. Subjects were also enrolled at the Department of Urology, University Hospital of Tours and at Clinik Donaustadt in Vienna. This study involves an ex vivo (outside a living organism) microdialysis procedure to measure the concentration of gepotidacin in tissues removed during surgery. The study completed enrollment in May 2023 with a total of 48 subjects enrolled and receiving a single dose of gepotidacin. Data from this study indicated that gepotidacin is distributed to prostate and tonsil tissue after an oral dose and provided information on how the concentration in these tissues changes over time.
At the University of Poitiers, using the data from both animal model and clinical studies, we have developed models that enable us to predict tissue exposure in humans after various doses and relate that to the effect of the drug. These models allow us to extrapolate between species so that we can translate future animal model data to expand our knowledge beyond the human study that is limited to a single time point per individual. These models will be a critical tool for future gepotidacin dose selection when considering infections where tissue distribution is likely to play an important role in efficacy, for example in infections of the throat or prostate.
These valuable scientific data were generated as a result of the diversity of thought and experience and the excellent collaboration between the partners in this IMI project. The success of this project highlights the importance of public-private partnerships to deliver innovative science in this area.
As described above, the project has provided tools which will be used to assess the potential of this novel antibacterial as a treatment option for bacterial infections of the tonsil or prostate and will have the following potential impacts, as detailed at the start of the project:
- 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.
However, we need to be clear that although tissue penetration is one important aspect of an effective treatment for bacterial infections of the tonsil or prostate, it does not in itself indicate clinical efficacy.
- 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.
However, we need to be clear that although tissue penetration is one important aspect of an effective treatment for bacterial infections of the tonsil or prostate, it does not in itself indicate clinical efficacy.