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Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria

BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patien...

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Autores principales: Goulooze, Sebastiaan Camiel, Snelder, Nelleke, Seelmann, Andreas, Horvat-Broecker, Andrea, Brinker, Meike, Joseph, Amer, Garmann, Dirk, Lippert, Joerg, Eissing, Thomas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891103/
https://www.ncbi.nlm.nih.gov/pubmed/34786651
http://dx.doi.org/10.1007/s40262-021-01083-1
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author Goulooze, Sebastiaan Camiel
Snelder, Nelleke
Seelmann, Andreas
Horvat-Broecker, Andrea
Brinker, Meike
Joseph, Amer
Garmann, Dirk
Lippert, Joerg
Eissing, Thomas
author_facet Goulooze, Sebastiaan Camiel
Snelder, Nelleke
Seelmann, Andreas
Horvat-Broecker, Andrea
Brinker, Meike
Joseph, Amer
Garmann, Dirk
Lippert, Joerg
Eissing, Thomas
author_sort Goulooze, Sebastiaan Camiel
collection PubMed
description BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium. METHODS: Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose–exposure–response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements. RESULTS: Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose–exposure–potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase. CONCLUSIONS: The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01083-1.
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spelling pubmed-88911032022-03-08 Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria Goulooze, Sebastiaan Camiel Snelder, Nelleke Seelmann, Andreas Horvat-Broecker, Andrea Brinker, Meike Joseph, Amer Garmann, Dirk Lippert, Joerg Eissing, Thomas Clin Pharmacokinet Original Research Article BACKGROUND: Finerenone is a nonsteroidal selective mineralocorticoid receptor antagonist (MRA) that demonstrated efficacy in delaying the progression of chronic kidney disease (CKD) and reducing cardiovascular events in patients with CKD and type 2 diabetes mellitus in FIDELIO-DKD, where 5734 patients were randomized 1:1 to receive either finerenone or placebo, with a median follow-up of 2.6 years. Doses of finerenone 10 or 20 mg once daily were titrated based on (serum) potassium and estimated glomerular filtration rate. The MRA mode of action increases potassium. METHODS: Nonlinear mixed-effects population pharmacokinetic/pharmacodynamic models were used to analyze the finerenone dose–exposure–response relationship for potassium in FIDELIO-DKD. Individual time-varying exposures from pharmacokinetic analyses were related to the potassium response via a maximal effect, indirect-response model informed by 148,384 serum potassium measurements. RESULTS: Although observed potassium levels decreased with increasing dose (i.e., inverse relation), model-based simulations for a fixed-dose setting (i.e., no dose titration) revealed the intrinsic finerenone dose–exposure–potassium response, with potassium levels increasing in a dose- and exposure-dependent manner, thus explaining the apparent conflict. The potassium limit for inclusion and uptitration from finerenone 10 to 20 mg in FIDELIO-DKD was ≤ 4.8 mmol/L. Modified limits of ≤ 5.0 mmol/L were simulated, resulting in higher hyperkalemia frequencies for both the finerenone and the placebo arms, whereas the relative hyperkalemia risk of a finerenone treatment compared with placebo did not increase. CONCLUSIONS: The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40262-021-01083-1. Springer International Publishing 2021-11-17 2022 /pmc/articles/PMC8891103/ /pubmed/34786651 http://dx.doi.org/10.1007/s40262-021-01083-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by-nc/4.0/Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Original Research Article
Goulooze, Sebastiaan Camiel
Snelder, Nelleke
Seelmann, Andreas
Horvat-Broecker, Andrea
Brinker, Meike
Joseph, Amer
Garmann, Dirk
Lippert, Joerg
Eissing, Thomas
Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title_full Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title_fullStr Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title_full_unstemmed Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title_short Finerenone Dose–Exposure–Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria
title_sort finerenone dose–exposure–serum potassium response analysis of fidelio-dkd phase iii: the role of dosing, titration, and inclusion criteria
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8891103/
https://www.ncbi.nlm.nih.gov/pubmed/34786651
http://dx.doi.org/10.1007/s40262-021-01083-1
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