Indications
In the United States, finerenone is prescribed to minimize the risk of a persistent decline in glomerular filtration rate, progression to end-stage kidney disease, cardiovascular death, myocardial infarction, and hospital admissions due to heart failure in adult patients with chronic kidney disease (CKD) associated with type 2 diabetes mellitus. Similarly, in Europe, finerenone is approved for managing·hronic kidney disease, specifically in stages 3 and 4 with albuminuria, in adult patients with type 2 diabetes. These indications highlight finerenone's crucial role in addressing·he concomitant challeng·harmacodynamics
Finerenone functions as a non-steroidal mineralocorticoid receptor antagonist. Its primary therapeutic action is to reduce the risk of sustained decline in glomerular filtration rate, progression to end-stage kidney disease, cardiovascular mortality, myocardial infarctions, and heart failure-related hospitalizations in adults suffering·hronic kidney disease with concurrent type 2 diabetes mellitus. Finerenone exhibits a moderate duration of action, suitable for a once-daily dosing·herapeutic window, with studied doses rang·hould be advised about the potential risk of hyperkalemia, necessitating·hieves a maximum plasma concentration (Cmax) of 351 µg/L, with a time to reach this concentration (Tmax) of approximately 1.5 hours and an area under the curve (AUC) of 2820 µg*h/L in plasma. In whole blood, the same dose yields a Cmax of 226 µg/L, with the Tmax and AUC mirroring·hose in plasma at 1.5 hours and 1840 µg*h/L, respectively. For regular dosing·hes a geometric mean steady-state Cmax of 160 µg/L with an AUC of 686 µg*h/L.
Metabolism
Finerenone is predominantly metabolized via the cytochrome P450 enzyme CYP3A4, contributing·hway, with CYP2C8 accounting·he remaining·here is a minor metabolic involvement by CYP1A1. Notably, finerenone does not produce active metabolites. The primary metabolic transformations include conversion to the M1 metabolite through aromatization by CYP3A4 and CYP2C8, followed by further hydroxylation to the M2 and subsequent oxidation to the M3 metabolite. Additional metabolic pathways involve epoxidation and hydrolysis leading·he M4 and subsequent metabolites. Furthermore, demethylation, oxidation, and ring·he M10 metabolite, while de-ethylation via CYP1A1 results in the M13 metabolite, along·her multi-step processes governed by CYP2C8 and CYP3A4 yielding·her metabolites.
Mechanism of Action
Finerenone is a non-steroidal, selective antagonist of the mineralocorticoid receptor (MR) that demonstrates no significant affinity or activity towards androgen, progesterone, estrogen, or glucocorticoid receptors. Animal studies have indicated that finerenone's interaction with the MR can reduce inflammation and fibrosis, while Phase 2 clinical trials have shown it can decrease albuminuria. The mineralocorticoid hormone aldosterone plays a crucial role in regulating blood pressure, sodium reabsorption, and potassium excretion. Historically, in 1943, the activation of the MR, combined with increased salt intake, was linked to malignant hypertension, potentially leading to inflammation and fibrosis in organs. When aldosterone binds to the MR, it induces a conformational shift, dissociating the receptor from its inactivating chaperone proteins. This active MR then translocates to the nucleus, joining a complex of coactivators to initiate the transcription of multiple genes. Finerenone inhibits the binding of MR coactivators, thereby preventing the transcription of genes associated with pro-inflammatory and pro-fibrotic pathways. Clinical trial data suggest that blocking the mineralocorticoid receptor can reduce mortality and morbidity in patients with chronic severe congestive heart failure, particularly those with an ejection fraction of 35% or less. Specifically, patients on finerenone exhibited a reduced incidence of new-onset atrial fibrillation or flutter (AFF) with a hazard ratio of 0.71. Furthermore, finerenone has been associated with a lower risk of initial kidney failure onset, a sustained eGFR reduction of 40% or more, or death from renal causes, with a hazard ratio of 0.82. It also improved cardiovascular outcomes, including cardiovascular death, nonfatal heart attacks, nonfatal strokes, and hospitalization for heart failure, with hazard ratios of 0.86 in patients with a history of AFF and 0.85 in those without.
