Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Bader, Justin C., Lakota, Elizabeth A., Flanagan, Shawn, Ong, Voon, Sandison, Taylor, Rubino, Christopher M., Bhavnani, Sujata M., Ambrose, Paul G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2018
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
_version_ 1783326300715352064
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
work_keys_str_mv AT baderjustinc overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT lakotaelizabetha overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT flanaganshawn overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT ongvoon overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT sandisontaylor overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT rubinochristopherm overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT bhavnanisujatam overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata
AT ambrosepaulg overcomingtheresistancehurdlepharmacokineticpharmacodynamictargetattainmentanalysesforrezafungincd101againstcandidaalbicansandcandidaglabrata