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Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin
Fungal infections pose a significant public health burden with high morbidity and mortality. CD101 is a novel echinocandin under development for the treatment and prevention of systemic Candida infections. Preclinical studies were conducted to evaluate the metabolic stability, plasma protein binding...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075098/ https://www.ncbi.nlm.nih.gov/pubmed/27620474 http://dx.doi.org/10.1128/AAC.00701-16 |
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author | Ong, Voon Hough, Grayson Schlosser, Michael Bartizal, Ken Balkovec, James M. James, Kenneth D. Krishnan, B. Radha |
author_facet | Ong, Voon Hough, Grayson Schlosser, Michael Bartizal, Ken Balkovec, James M. James, Kenneth D. Krishnan, B. Radha |
author_sort | Ong, Voon |
collection | PubMed |
description | Fungal infections pose a significant public health burden with high morbidity and mortality. CD101 is a novel echinocandin under development for the treatment and prevention of systemic Candida infections. Preclinical studies were conducted to evaluate the metabolic stability, plasma protein binding, pharmacokinetics, toxicity, and efficacy of CD101 at various dose levels. CD101 was stable to biotransformation in rat, monkey, and human liver microsomes and rat, monkey, dog, and human hepatocytes. In vitro studies suggest minimal interaction with recombinant cytochrome P450 enzymes (50% inhibitory concentrations [IC(50)s] of >10 μM). Similar to anidulafungin, CD101 bound avidly (>98%) to human, mouse, rat, and primate plasma proteins. In a 2-week repeat-dose comparison study, CD101 was well tolerated in rats (no effects on body weight, hematology, coagulation, or urinalysis). In contrast, administration of anidulafungin (at comparable exposure levels) resulted in reduced body weight, decreases in red blood cell, hemoglobin, hematocrit, mean cell volume, mean corpuscular hemoglobin, platelet, and reticulocyte counts, increases in neutrophil and eosinophil counts, polychromasia, and decreased activated partial thromboplastin time. Elevated plasma transaminases, total bilirubin, cholesterol, and globulin, dark and enlarged spleens, and single-cell hepatocyte necrosis were also observed for anidulafungin but not CD101. Hepatotoxicity may be due to the inherent chemical lability of anidulafungin generating potentially reactive intermediates. A glutathione trapping experiment confirmed the formation of a reactive species from anidulafungin, whereas CD101 did not exhibit instability or reactive intermediates. CD101 showed antifungal activity against Candida and Aspergillus infections in neutropenic mice. These preclinical studies demonstrated that CD101 is chemically and metabolically stable, well tolerated with no hepatotoxicity, and efficacious as an antifungal agent. |
format | Online Article Text |
id | pubmed-5075098 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-50750982016-11-11 Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin Ong, Voon Hough, Grayson Schlosser, Michael Bartizal, Ken Balkovec, James M. James, Kenneth D. Krishnan, B. Radha Antimicrob Agents Chemother Experimental Therapeutics Fungal infections pose a significant public health burden with high morbidity and mortality. CD101 is a novel echinocandin under development for the treatment and prevention of systemic Candida infections. Preclinical studies were conducted to evaluate the metabolic stability, plasma protein binding, pharmacokinetics, toxicity, and efficacy of CD101 at various dose levels. CD101 was stable to biotransformation in rat, monkey, and human liver microsomes and rat, monkey, dog, and human hepatocytes. In vitro studies suggest minimal interaction with recombinant cytochrome P450 enzymes (50% inhibitory concentrations [IC(50)s] of >10 μM). Similar to anidulafungin, CD101 bound avidly (>98%) to human, mouse, rat, and primate plasma proteins. In a 2-week repeat-dose comparison study, CD101 was well tolerated in rats (no effects on body weight, hematology, coagulation, or urinalysis). In contrast, administration of anidulafungin (at comparable exposure levels) resulted in reduced body weight, decreases in red blood cell, hemoglobin, hematocrit, mean cell volume, mean corpuscular hemoglobin, platelet, and reticulocyte counts, increases in neutrophil and eosinophil counts, polychromasia, and decreased activated partial thromboplastin time. Elevated plasma transaminases, total bilirubin, cholesterol, and globulin, dark and enlarged spleens, and single-cell hepatocyte necrosis were also observed for anidulafungin but not CD101. Hepatotoxicity may be due to the inherent chemical lability of anidulafungin generating potentially reactive intermediates. A glutathione trapping experiment confirmed the formation of a reactive species from anidulafungin, whereas CD101 did not exhibit instability or reactive intermediates. CD101 showed antifungal activity against Candida and Aspergillus infections in neutropenic mice. These preclinical studies demonstrated that CD101 is chemically and metabolically stable, well tolerated with no hepatotoxicity, and efficacious as an antifungal agent. American Society for Microbiology 2016-10-21 /pmc/articles/PMC5075098/ /pubmed/27620474 http://dx.doi.org/10.1128/AAC.00701-16 Text en Copyright © 2016 Ong et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Experimental Therapeutics Ong, Voon Hough, Grayson Schlosser, Michael Bartizal, Ken Balkovec, James M. James, Kenneth D. Krishnan, B. Radha Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title | Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title_full | Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title_fullStr | Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title_full_unstemmed | Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title_short | Preclinical Evaluation of the Stability, Safety, and Efficacy of CD101, a Novel Echinocandin |
title_sort | preclinical evaluation of the stability, safety, and efficacy of cd101, a novel echinocandin |
topic | Experimental Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5075098/ https://www.ncbi.nlm.nih.gov/pubmed/27620474 http://dx.doi.org/10.1128/AAC.00701-16 |
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