Pharmacokinetics and pharmacodynamics of finerenone in patients with chronic kidney disease and type 2 diabetes: Insights based on FIGARO‐DKD and FIDELIO‐DKD

Abstract

AimsTo perform dose–exposure–response analyses to determine the effects of finerenone doses.Materials and MethodsTwo randomized, double‐blind, placebo‐controlled phase 3 trials enrolling 13 026 randomized participants with type 2 diabetes (T2D) from global sites, each with an estimated glomerular filtration rate (eGFR) of 25 to 90 mL/min/1.73 m2, a urine albumin‐creatinine ratio (UACR) of 30 to 5000 mg/g, and serum potassium ≤ 4.8 mmol/L were included. Interventions were titrated doses of finerenone 10 or 20 mg versus placebo on top of standard of care. The outcomes were trajectories of plasma finerenone and serum potassium concentrations, UACR, eGFR and kidney composite outcomes, assessed using nonlinear mixed‐effects population pharmacokinetic (PK)/pharmacodynamic (PD) and parametric time‐to‐event models.ResultsFor potassium, lower serum levels and lower rates of hyperkalaemia were associated with higher doses of finerenone 20 mg compared to 10 mg (p < 0.001). The PK/PD model analysis linked this observed inverse association to potassium‐guided dose titration. Simulations of a hypothetical trial with constant finerenone doses revealed a shallow but increasing exposure–potassium response relationship. Similarly, increasing finerenone exposures led to less than dose‐proportional increasing reductions in modelled UACR. Modelled UACR explained 95% of finerenone's treatment effect in slowing chronic eGFR decline. No UACR‐independent finerenone effects were identified. Neither sodium‐glucose cotransporter‐2 (SGLT2) inhibitor nor glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) treatment significantly modified the effects of finerenone in reducing UACR and eGFR decline. Modelled eGFR explained 87% of finerenone's treatment effect on kidney outcomes. No eGFR‐independent effects were identified.ConclusionsThe analyses provide strong evidence for the effectiveness of finerenone dose titration in controlling serum potassium elevations. UACR and eGFR are predictive of kidney outcomes during finerenone treatment. Finerenone's kidney efficacy is independent of concomitant use of SGLT2 inhibitors and GLP‐1RAs.

Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials

“…The current results are supported by findings from a pharmacokinetics (PK) analysis based on FIDELIO-DKD and FIGARO-DKD data, in which both age and sex were tested as covariates for a population PK model, and their effect on finerenone exposure was not significant, suggesting a lack of influence of these factors on the PK of the drug. 30 Additionally, the results for the CV outcome in this analysis are similar to findings from other studies of MRAs in HF. In TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), age did not affect the efficacy of spironolactone in patients with HF with reduced ejection fraction (primary composite outcome: CV death, aborted cardiac arrest and HHF; secondary outcomes included CV death, all-cause death and HHF).…”

Role of Uremic Toxins, Oxidative Stress, and Renal Fibrosis in Chronic Kidney Disease

“…The recommended daily dose is 10–20 mg ×1 per day, depending on GFR and blood potassium levels, with all dose reductions requiring every 4 weeks monitoring of the aforementioned blood parameters [ 87 ]. Finerenone at a dose of 20 mg, in studies, correlated with lower blood potassium concentrations than with finereon at a dose of 10 mg [ 95 ]. As for the effect on blood pressure, it is small, while the drug makes up for it by having a strong proteinuria-reducing effect and showing great renal protection with a moderate risk of hyperkalemia [ 96 ].…”