Dose–Exposure–Response Analysis of Finerenone on Serum Potassium and Cardiovascular Outcomes Among Patients With Heart Failure: Insights From FINEARTS ‐ HF

Abstract

ABSTRACT Background Finerenone reduces the risk of heart failure and cardiovascular (CV) death among patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF). Whether the effects of finerenone to reduce CV risk are dose/exposure dependent is not clear. Methods In FINEARTS‐HF, 6001 participants were randomized to finerenone or placebo, where the initial and target dose of finerenone was titrated according to the baseline estimated glomerular filtration rate (eGFR; 10– > 20 mg if baseline eGFR ≤ 60; 20– > 40 mg if > 60 mL/min/1.73 m 2 ) and by serum potassium and changes in eGFR during the trial. We fitted non‐linear mixed‐effects population pharmacokinetic/pharmacodynamic and parametric repeated time‐to‐event models to explore the effect of finerenone dose on exposure ( n = 6658 plasma concentration measurements) and exposure on serum potassium ( n = 123 720 measurements), NT‐proBNP ( n = 16 971 measurements) and the primary composite outcome of total heart failure events and CV death ( n = 2366 events). Results The mean eGFR in those with an initial dose of 10 mg and 20 mg was 46 ± 12 and 76 ± 14 mL/min/1.73 m 2 , respectively. The frequency of hyperkalemia (> 5.5 mmol/L) was 4.3% in patients taking 10 mg finerenone, 2.7% among those taking 20 mg and 1.5% among those taking 40 mg. Simulated PK/PD data produced higher serum potassium with higher finerenone exposure in a hypothetical scenario without dose titration; however, when simulating the protocol‐guided dose titration strategy implemented in the trial, the lower observed frequency of hyperkalemia at higher finerenone exposure was explained. For the efficacy exposure–response analyses, while higher finerenone exposure was non‐significantly related to a lower frequency of CV composite events ( p = 0.55), higher exposure did result in a significantly greater reduction in NT‐proBNP concentrations ( p < 0.001). Conclusions Among participants of FINEARTS‐HF, finerenone dose titration was effective in managing serum potassium concentration. Although FINEARTS‐HF was not designed to test a randomized comparison of dose or exposure, the PK/PD model suggests that higher achieved exposure is associated with improved CV efficacy.