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716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)

BACKGROUND: Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of...

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Autores principales: Woo, Jennifer, Hearne, Ken, Kelson, Andy, Yee, Luisa, Espadas, Cecilia, Truong, Vu L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811032/
http://dx.doi.org/10.1093/ofid/ofz360.784
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author Woo, Jennifer
Hearne, Ken
Kelson, Andy
Yee, Luisa
Espadas, Cecilia
Truong, Vu L
author_facet Woo, Jennifer
Hearne, Ken
Kelson, Andy
Yee, Luisa
Espadas, Cecilia
Truong, Vu L
author_sort Woo, Jennifer
collection PubMed
description BACKGROUND: Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented. METHODS: MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates. RESULTS: In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route. CONCLUSION: In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501. [Image: see text] [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures.
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spelling pubmed-68110322019-10-28 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate) Woo, Jennifer Hearne, Ken Kelson, Andy Yee, Luisa Espadas, Cecilia Truong, Vu L Open Forum Infect Dis Abstracts BACKGROUND: Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented. METHODS: MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates. RESULTS: In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route. CONCLUSION: In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501. [Image: see text] [Image: see text] [Image: see text] [Image: see text] DISCLOSURES: All authors: No reported disclosures. Oxford University Press 2019-10-23 /pmc/articles/PMC6811032/ http://dx.doi.org/10.1093/ofid/ofz360.784 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Woo, Jennifer
Hearne, Ken
Kelson, Andy
Yee, Luisa
Espadas, Cecilia
Truong, Vu L
716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title_full 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title_fullStr 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title_full_unstemmed 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title_short 716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
title_sort 716. in vitro and in vivo nonclinical efficacy of ar-501 (gallium citrate)
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811032/
http://dx.doi.org/10.1093/ofid/ofz360.784
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