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- Title
Finerenone Dose-Exposure-Serum Potassium Response Analysis of FIDELIO-DKD Phase III: The Role of Dosing, Titration, and Inclusion Criteria.
- Authors
Goulooze, Sebastiaan Camiel; Snelder, Nelleke; Seelmann, Andreas; Horvat-Broecker, Andrea; Brinker, Meike; Joseph, Amer; Garmann, Dirk; Lippert, Joerg; Eissing, Thomas
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>The analyses demonstrated the effectiveness of finerenone dose titration in managing serum potassium and provide a quantitative basis to guide safe clinical use.
- Subjects
POTASSIUM; TYPE 2 diabetes; MINERALOCORTICOID receptors; VOLUMETRIC analysis; GLOMERULAR filtration rate
- Publication
Clinical Pharmacokinetics, 2022, Vol 61, Issue 3, p451
- ISSN
0312-5963
- Publication type
journal article
- DOI
10.1007/s40262-021-01083-1