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Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata
Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate sin...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971579/ https://www.ncbi.nlm.nih.gov/pubmed/29555634 http://dx.doi.org/10.1128/AAC.02614-17 |
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author | Bader, Justin C. Lakota, Elizabeth A. Flanagan, Shawn Ong, Voon Sandison, Taylor Rubino, Christopher M. Bhavnani, Sujata M. Ambrose, Paul G. |
author_facet | Bader, Justin C. Lakota, Elizabeth A. Flanagan, Shawn Ong, Voon Sandison, Taylor Rubino, Christopher M. Bhavnani, Sujata M. Ambrose, Paul G. |
author_sort | Bader, Justin C. |
collection | PubMed |
description | Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log(10) CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC(90) for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC(100) values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata. |
format | Online Article Text |
id | pubmed-5971579 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-59715792018-05-31 Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata Bader, Justin C. Lakota, Elizabeth A. Flanagan, Shawn Ong, Voon Sandison, Taylor Rubino, Christopher M. Bhavnani, Sujata M. Ambrose, Paul G. Antimicrob Agents Chemother Clinical Therapeutics Rezafungin (CD101) is a novel echinocandin antifungal agent with activity against Aspergillus and Candida species, including azole- and echinocandin-resistant isolates. The objective of these analyses was to conduct pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analyses to evaluate single and once-weekly rezafungin dosing to provide dose selection support for future clinical studies. Using a previously developed rezafungin population PK model, Monte Carlo simulations were conducted utilizing the following three intravenous rezafungin regimens: (i) a single 400 mg dose, (ii) 400 mg for week 1 followed by 200 mg weekly for 5 weeks, and (iii) 400 mg weekly for 6 weeks. Percent probabilities of achieving the nonclinical PK-PD targets associated with net fungal stasis and 1-log(10) CFU reductions from baseline for Candida albicans and Candida glabrata were calculated for each rezafungin regimen. At the MIC(90) for C. albicans and C. glabrata, a single 400 mg dose of rezafungin achieved probabilities of PK-PD target attainment of ≥90% through week 3 of therapy for all PK-PD targets evaluated. When evaluating the multiple-dose (i.e., weekly) regimens under these conditions, percent probabilities of PK-PD target attainment of 100% were achieved through week 6. Moreover, high (>90%) probabilities of PK-PD target attainment were achieved through week 6 following administration of the weekly regimens at or above the MIC(100) values for C. albicans and C. glabrata based on contemporary in vitro surveillance data. These analyses support the use of single and once-weekly rezafungin regimens for the treatment of patients with candidemia and/or candidiasis due to C. albicans or C. glabrata. American Society for Microbiology 2018-05-25 /pmc/articles/PMC5971579/ /pubmed/29555634 http://dx.doi.org/10.1128/AAC.02614-17 Text en Copyright © 2018 Bader et al. https://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 (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Clinical Therapeutics Bader, Justin C. Lakota, Elizabeth A. Flanagan, Shawn Ong, Voon Sandison, Taylor Rubino, Christopher M. Bhavnani, Sujata M. Ambrose, Paul G. Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title | Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title_full | Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title_fullStr | Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title_full_unstemmed | Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title_short | Overcoming the Resistance Hurdle: Pharmacokinetic-Pharmacodynamic Target Attainment Analyses for Rezafungin (CD101) against Candida albicans and Candida glabrata |
title_sort | overcoming the resistance hurdle: pharmacokinetic-pharmacodynamic target attainment analyses for rezafungin (cd101) against candida albicans and candida glabrata |
topic | Clinical Therapeutics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5971579/ https://www.ncbi.nlm.nih.gov/pubmed/29555634 http://dx.doi.org/10.1128/AAC.02614-17 |
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