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Goulooze SC, Snelder N, Seelmann A, et al. Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria. Clin Pharmacokinet. 2021;doi: 10.1007/s40262-021-01083-1.
Goulooze, S. C., Snelder, N., Seelmann, A., Horvat-Broecker, A., Brinker, M., Joseph, A., Garmann, D., Lippert, J., & Eissing, T. (2021). Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria. Clinical pharmacokinetics, . https://doi.org/10.1007/s40262-021-01083-1
Goulooze, Sebastiaan Camiel, et al. "Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria." Clinical pharmacokinetics vol. (2021). doi: https://doi.org/10.1007/s40262-021-01083-1
Goulooze SC, Snelder N, Seelmann A, Horvat-Broecker A, Brinker M, Joseph A, Garmann D, Lippert J, Eissing T. Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria. Clin Pharmacokinet. 2021 Nov 17; doi: 10.1007/s40262-021-01083-1. Epub 2021 Nov 17. PMID: 34786651.
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Clin Pharmacokinet. 2021 Nov 17; doi: 10.1007/s40262-021-01083-1. Epub 2021 Nov 17.

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

Clinical pharmacokinetics

Sebastiaan Camiel Goulooze, Nelleke Snelder, Andreas Seelmann, Andrea Horvat-Broecker, Meike Brinker, Amer Joseph, Dirk Garmann, Joerg Lippert, Thomas Eissing

Affiliations

  1. Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands.
  2. Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Leverkusen/Wuppertal/Berlin, Germany.
  3. Bayer AG, Pharmaceuticals R&D, Pharmacovigilance, Wuppertal, Germany.
  4. Bayer AG, Pharmaceuticals R&D, Clinical Development, Wuppertal/Berlin, Germany.
  5. Bayer AG, Pharmaceuticals R&D, Pharmacometrics, Leverkusen/Wuppertal/Berlin, Germany. [email protected].

PMID: 34786651 DOI: 10.1007/s40262-021-01083-1

Abstract

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.

© 2021. The Author(s).

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