Finerenone

Breast Feeding; Lactation; Mineralocorticoid Receptor Antagonists

FDA approved drugs -> Active ingredient

EMA approved medicines: Human medicine

FDA approved drugs -> Active ingredient

Danger

H301 (100%): Toxic if swallowed [Danger Acute toxicity, oral]

P203, P260, P263, P264, P270, P273, P280, P301+P316, P318, P319, P321, P330, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 3 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

In placebo-controlled trials of finerenone in several thousand patients, there was usually no mention of serum enzyme elevations or hepatotoxicity. In the largest placebo controlled trial, the rate of “hepatobiliary” adverse events was similar in patients on finerenone compared to placebo (4.4% vs 4.8%), and there were no reported hepatic serious adverse events. Since its approval and more widespread use, finerenone has not been implicated in instances of acute hepatic injury and the product label does not mention aminotransferase elevations or clinically apparent liver injury in lists of potential adverse events.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Finerenone

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

C - Cardiovascular system

QC - Cardiovascular system

Finerenone is a non-steroidal mineralocorticoid receptor antagonist indicated to reduce the risk of sustained decline in glomerular filtration rate, end stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with chronic kidney disease associated with type II diabetes mellitus. It has a moderate duration of action as it is taken once daily, and a wide therapeutic window as patients were given doses from 1.25 mg to 80 mg in clinical trials. Patients should be counselled regarding the risk of hyperkalemia.

Finerenone is a non-steroidal selective mineralocorticoid receptor (MR) antagonist with no significant affinity or activity at androgen, progesterone, estrogen, and glucocorticoid receptors. Animal studies have shown that finerenone binding to the MR reduces inflammation and fibrosis, and phase 2 clinical trials showed a reduction in albuminuria. Aldosterone is a mineralocorticoid hormone involved in the regulation of blood pressure, sodium reabsorption, and potassium excretion. In 1943, agonism of the MR along with increased salt was shown to be associated with malignant hypertension, which could progress to inflammation and fibrosis of organs. Binding of aldosterone, an MR agonist, to the MR causes a conformational change, which dissociates the receptor from inactivating chaperone proteins. The active MR translocates to the nucleus along with a complex of other coactivators to induce transcription of a number of genes. Finerenone's binding to the MR prevents binding of MR coactivators, which in turn prevents pro-inflammatory and pro-fibrotic gene transcription. Clinical trial data shows that blocking the mineralocorticoid receptor reduces mortality and morbidity in patients with chronic severe congestive heart failure with an ejection fraction ≤35%. Patients taking finerenone developed new onset atrial fibrillation or flutter (AFF) with a hazard ratio of 0.71. Finerenone lowered the risk of first onset of kidney failure, a sustained eGFR decrease of ≥40%, or death from a renal cause to a hazard ratio of 0.82. Cardiovascular outcomes including cardiovascular death, nonfatal heart attacks, nonfatal strokes, and hospitalization for heart failure in patients taking finerenone had a hazard ratio of 0.86 in patients with a history of AFF and 0.85 in patients without a history of AFF.

Finerenone is approximately 90% metabolized by CYP3A4, and 10% metabolized by CYP2C8. There is a minor contribution to metabolism by CYP1A1. Finerenone has no active metabolites. Finerenone is aromatized to the M1 metabolite by CYP3A4 and CYP2C8, which is further hydroxylated by CYP3A4 to the M2 metabolite, and finally oxidized bye CYP3A4 to the M3 metabolite. Alternatively, finerenone can undergo epoxidation and possibly hydrolysis by CYP3A4 and CYP2C8 to form the M4 metabolite, which is hydroxylated again by CYP3A4 to the M5 metabolite, and oxidized to the M8 metabolite. Finerenone can also be hydroxylated by CYP2C8 to the M7 metabolite, and further oxidized to the M9 metabolite. The M10 metabolite is formed by the demethylation, oxidation, and ring opening of finerenone. The M13 metabolite is formed through de-ethylation of finerenone by CYP1A1, and the M14 metabolite is formed through an undefined multi-step process involving CYP2C8 and CYP3A4.

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FINERENONE

Established Pharmacologic Class [EPC] - Nonsteroidal Mineralocorticoid-Receptor Antagonist

Mechanisms of Action [MoA] - Mineralocorticoid Receptor Antagonists

Finerenone is a Nonsteroidal Mineralocorticoid-Receptor Antagonist. The mechanism of action of finerenone is as a Mineralocorticoid Receptor Antagonist.

FINERENONE

A 10 mg oral dose of finerenone reaches a Cmax of 351 µg/L, with a Tmax of 1.5 hours, and an AUC of 2820 µg\*h/L in plasma. The same dose of finerenone reaches a Cmax of 226 µg/L, with a Tmax of 1.5 hours, and an AUC of 1840 µg\*h/L in whole blood. Regular doses of 20 mg of finerenone reach a geometric mean steady state Cmax of 160 µg/L with an AUC of 686 µg\*h/L.

The majority of the dose recovered in urine was in the form of the M2, M3 (47.8%), and M4 metabolites; <1.3% of the dose recovered in the urine was as the unchanged parent compound. The majority of the dose recovered in the feces was as the M5 metabolite, with only 0.2% eliminated as the unchanged parent compound. The M1 metabolite made up <1.5% of the recovered dose in urine and feces. Finerenone is not expected to be metabolized by the intestinal microflora.

The volume of distribution of finerenone as steady state is 52.6L.

The systemic clearance of finerenone is approximately 25 L/h.