Finerenone

Identification

Summary

Finerenone is a nonsteroidal mineralocorticoid receptor antagonist indicated to lower the risk of eGFR decline, end stage kidney disease, cardiovascular death, heart attack, and hospitalization for heart failure in chronic kidney disease associated with type 2 diabetes.

Brand Names

Kerendia

Generic Name

Finerenone

DrugBank Accession Number

DB16165

Background

Finerenone, or BAY 94-8862, is a 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.^1,7 Patients with kidney disease, would originally be given spironolactone or eplerenone to antagonize the mineraclocorticoid receptor.⁶ Spironolactone has low selectivity and affinity for the receptor; it dissociates quickly and can also have effects at the androgen, progesterone, and glucocorticoid receptors.⁶ Eplerenone is more selective and has longer lasting effects.⁶ More selective nonsteroidal mineralocorticoid antagonists such as apararenone, esaxerenone, and finerenone were later developed.⁶ So far, finerenone is the only nonsteroidal mineralocorticoid receptor antagonist to be FDA approved.^6,7

Finerenone was granted FDA approval on 9 July 2021,⁷ followed by the EMA approval on 11 March 2022.⁹

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Finerenone (DB16165)

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Weight

Average: 378.432
Monoisotopic: 378.169190584

Chemical Formula

C₂₁H₂₂N₄O₃

Synonyms

• Finerenone

External IDs

• BAY 94-8862
• BAY-94-8862

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Pharmacology

Indication

In the US, finerenone is 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.⁷

In Europe, finerenone is indicated for the treatment of chronic kidney disease (stage 3 and 4 with albuminuria) associated with type 2 diabetes in adults.⁸

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Prophylaxis of	Cardiovascular mortality		••••••••••••	•••••	•••• • •••••••• ••••••••• ••••••• •••••• ••••••• •••••	••••••
Management of	Chronic kidney disease, stage 3 (moderate)		••••••••••••	•••••	•••••••••••	••••••
Prophylaxis of	End-stage kidney disease		••••••••••••	•••••	•••• • •••••••• ••••••••• ••••••• •••••• ••••••• •••••	••••••
Prophylaxis of	Hospitalizations		••••••••••••	•••••	•••• • •••••••• ••••••••• ••••••• •••••• ••••••• •••••	••••••
Management of	Stage 4 chronic kidney disease		••••••••••••	•••••	•••••••••••	••••••

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Pharmacodynamics

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.⁷ 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.⁷ Patients should be counselled regarding the risk of hyperkalemia.⁷

Mechanism of action

Finerenone is a non-steroidal selective mineralocorticoid receptor (MR) antagonist with no significant affinity or activity at androgen, progesterone, estrogen, and glucocorticoid receptors.^2,7 Animal studies have shown that finerenone binding to the MR reduces inflammation and fibrosis, and phase 2 clinical trials showed a reduction in albuminuria.^2,3

Aldosterone is a mineralocorticoid hormone involved in the regulation of blood pressure, sodium reabsorption, and potassium excretion.² 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.²

Binding of aldosterone, an MR agonist, to the MR causes a conformational change, which dissociates the receptor from inactivating chaperone proteins.⁵ The active MR translocates to the nucleus along with a complex of other coactivators to induce transcription of a number of genes.⁵

Finerenone's binding to the MR prevents binding of MR coactivators, which in turn prevents pro-inflammatory and pro-fibrotic gene transcription.^2,3

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%.⁴ Patients taking finerenone developed new onset atrial fibrillation or flutter (AFF) with a hazard ratio of 0.71.³ 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 0.82.³ 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.³

Target	Actions	Organism
AMineralocorticoid receptor	antagonist	Humans

Absorption

A 10 mg oral dose of finerenone reaches a C_max of 351 µg/L, with a T_max of 1.5 hours, and an AUC of 2820 µg*h/L in plasma.¹ The same dose of finerenone reaches a C_max of 226 µg/L, with a T_max of 1.5 hours, and an AUC of 1840 µg*h/L in whole blood.¹

Regular doses of 20 mg of finerenone reach a geometric mean steady state C_max of 160 µg/L with an AUC of 686 µg*h/L.⁷

Volume of distribution

The volume of distribution of finerenone as steady state is 52.6L.⁷

Protein binding

Finerenone is 92% protein bound in plasma; predominantly to serum albumin.⁷

Metabolism

Finerenone is approximately 90% metabolized by CYP3A4, and 10% metabolized by CYP2C8.^1,7 There is a minor contribution to metabolism by CYP1A1.¹ Finerenone has no active metabolites.²

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.¹ 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.¹ Finerenone can also be hydroxylated by CYP2C8 to the M7 metabolite, and further oxidized to the M9 metabolite.¹

The M10 metabolite is formed by the demethylation, oxidation, and ring opening of finerenone.¹ 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 CYP3A4.¹

Hover over products below to view reaction partners

• Finerenone
  • Finerenone M13 Metabolite
  • Finerenone M14 Metabolite
  • Finerenone M1 Metabolite
    • Finerenone M2 Metabolite
      • Finerenone M3 Metabolite
  • Finerenone M10 Metabolite
  • Finerenone M4 Metabolite
    • Finerenone M5 Metabolite
      • Finerenone M8 Metabolite

Route of elimination

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.¹ The majority of the dose recovered in the feces was as the M5 metabolite, with only 0.2% eliminated as the unchanged parent compound.¹ The M1 metabolite made up <1.5% of the recovered dose in urine and feces.¹

Finerenone is not expected to be metabolized by the intestinal microflora.¹

Half-life

The half life of a 10 mg dose of finerenone in 4 healthy men was 17.4 hours in plasma and 12.3 hours in whole blood.¹ The terminal half life of finerenone is approximately 2-3 hours.⁷

Clearance

The systemic clearance of finerenone is approximately 25 L/h.⁷

Adverse Effects

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Toxicity

Patients experiencing an overdose of finerenone may experience hyperkalemia.⁷ In the even of an overdose, immediately stop taking finerenone.⁷ Treat patients with symptomatic and supportive treatment, including treatment for hyperkalemia if it develops.⁷ Hemodialysis is not expected to remove finerenone from the blood due to its high plasma protein binding.⁷

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Finerenone may increase the excretion rate of Abacavir which could result in a lower serum level and potentially a reduction in efficacy.
Abametapir	The serum concentration of Finerenone can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Finerenone can be increased when combined with Abatacept.
Abiraterone	The metabolism of Finerenone can be decreased when combined with Abiraterone.
Acalabrutinib	The serum concentration of Finerenone can be increased when it is combined with Acalabrutinib.

Food Interactions

• Avoid grapefruit products. Grapefruit products may increase exposure to finerenone, increasing the risk and severity of adverse effects.
• Take with or without food. Food does not have a clinically significant effect on area under the curve.

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International/Other Brands

Kerendia (Bayer)

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Kerendia	Tablet, film coated	20 mg	Oral	Bayer Ag	2022-05-04	Not applicable
Kerendia	Tablet	20 mg	Oral	Bayer	2022-11-22	Not applicable
Kerendia	Tablet, film coated	20 mg	Oral	Bayer Ag	2022-05-04	Not applicable
Kerendia	Tablet, film coated	10 mg	Oral	Bayer Ag	2022-05-04	Not applicable
Kerendia	Tablet, film coated	20 mg	Oral	Bayer Ag	2022-05-04	Not applicable

Categories

ATC Codes

C03DA05 — Finerenone

• C03DA — Aldosterone antagonists
• C03D — ALDOSTERONE ANTAGONISTS AND OTHER POTASSIUM-SPARING AGENTS
• C03 — DIURETICS
• C — CARDIOVASCULAR SYSTEM

Drug Categories

• Agents causing hyperkalemia
• Cytochrome P-450 CYP2C8 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Diuretics
• Heterocyclic Compounds, Fused-Ring
• Mineralocorticoid Receptor Antagonists
• Nonsteroidal Mineralocorticoid-Receptor Antagonist

Classification

Not classified

Affected organisms

• Humans

Chemical Identifiers

UNII

DE2O63YV8R

CAS number

1050477-31-0

InChI Key

BTBHLEZXCOBLCY-QGZVFWFLSA-N

InChI

InChI=1S/C21H22N4O3/c1-5-28-21-18-17(14-7-6-13(9-22)8-15(14)27-4)16(20(23)26)12(3)25-19(18)11(2)10-24-21/h6-8,10,17,25H,5H2,1-4H3,(H2,23,26)/t17-/m1/s1

IUPAC Name

(4S)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide

SMILES

CCOC1=NC=C(C)C2=C1[C@H](C1=CC=C(C=C1OC)C#N)C(C(N)=O)=C(C)N2

References

General References

1. Gerisch M, Heinig R, Engelen A, Lang D, Kolkhof P, Radtke M, Platzek J, Lovis K, Rohde G, Schwarz T: Biotransformation of Finerenone, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, in Dogs, Rats, and Humans, In Vivo and In Vitro. Drug Metab Dispos. 2018 Nov;46(11):1546-1555. doi: 10.1124/dmd.118.083337. Epub 2018 Aug 31. [Article]
2. Epstein M: Aldosterone and Mineralocorticoid Receptor Signaling as Determinants of Cardiovascular and Renal Injury: From Hans Selye to the Present. Am J Nephrol. 2021;52(3):209-216. doi: 10.1159/000515622. Epub 2021 Apr 15. [Article]
3. Filippatos G, Bakris GL, Pitt B, Agarwal R, Rossing P, Ruilope LM, Butler J, Lam CSP, Kolkhof P, Roberts L, Tasto C, Joseph A, Anker SD: Finerenone Reduces New-Onset Atrial Fibrillation in Patients With Chronic Kidney Disease and Type 2 Diabetes. J Am Coll Cardiol. 2021 Jul 13;78(2):142-152. doi: 10.1016/j.jacc.2021.04.079. Epub 2021 May 17. [Article]
4. Li Z, Zhao H, Wang J: Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities. Front Cardiovasc Med. 2021 May 5;8:650278. doi: 10.3389/fcvm.2021.650278. eCollection 2021. [Article]
5. Yang J, Young MJ: The mineralocorticoid receptor and its coregulators. J Mol Endocrinol. 2009 Aug;43(2):53-64. doi: 10.1677/JME-09-0031. [Article]
6. Vodosek Hojs N, Bevc S, Ekart R, Piko N, Petreski T, Hojs R: Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease. Pharmaceuticals (Basel). 2021 Jun 11;14(6). pii: ph14060561. doi: 10.3390/ph14060561. [Article]
7. FDA Approved Drug Products: Kerendia (Finerenone) Oral Tablet [Link]
8. EMA Approved Drug Products: Kerendia (finerenone) Oral Tablets [Link]
9. European Medicines Agency Medicines: Kerendia (finerenone) [Link]

External Links

ChemSpider

28669387

RxNav

2562811

ChEMBL

CHEMBL2181927

Wikipedia

Finerenone

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Chronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus	1
4	Not Yet Recruiting	Treatment	Albuminuria / Chronic Kidney Disease (CKD) / Chronic Kidney Disease Due to Type 2 Diabetes Mellitus / Chronic Kidney Disease, Stage 3 (Moderate) / CKD / CKD Stage 3 / Diabetes / Diabetes Complications / Diabetes Mellitus / Diabetes Mellitus Type 2 With Proteinuria / Stage 4 Chronic Kidney Disease / Type 2 Diabetes Mellitus	1
4	Not Yet Recruiting	Treatment	Hypertension / Primary Aldosteronism	1
4	Not Yet Recruiting	Treatment	Primary Aldosteronism	1
4	Recruiting	Treatment	Chronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	10.000 mg
Tablet	Oral	10 mg
Tablet	Oral	20 mg
Tablet, film coated	Oral	10 mg/1
Tablet, film coated	Oral	20 mg/1
Tablet, film coated	Oral	10 mg
Tablet, film coated	Oral	20 mg

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8436180	No	2013-05-07	2029-04-12

Properties

State

Solid

Experimental Properties

Not Available

Predicted Properties

Property	Value	Source
Water Solubility	0.0354 mg/mL	ALOGPS
logP	2.21	ALOGPS
logP	1.85	Chemaxon
logS	-4	ALOGPS
pKa (Strongest Acidic)	14.87	Chemaxon
pKa (Strongest Basic)	6.06	Chemaxon
Physiological Charge	0	Chemaxon
Hydrogen Acceptor Count	6	Chemaxon
Hydrogen Donor Count	2	Chemaxon
Polar Surface Area	110.26 Å2	Chemaxon
Rotatable Bond Count	5	Chemaxon
Refractivity	109.13 m3·mol-1	Chemaxon
Polarizability	39.66 Å3	Chemaxon
Number of Rings	3	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	No	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0009000000-fd01ad01cb20e65a0659
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0a4i-0009000000-29282602ee7e486ec1c4
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-01t9-0009000000-16ab2c3e3fe4bc2b83e4
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-004i-1009000000-c4256969f4e8e6d3c786
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-004i-0798000000-74a1bf3b3175728c74d8
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0uyi-1039000000-916e263e2a4014db7cbd
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Adduct	CCS Value (Å2)	Source type	Source
[M-H]-	205.2665676	predicted	DarkChem Lite v0.1.0
[M+H]+	205.9463676	predicted	DarkChem Lite v0.1.0
[M+Na]+	205.4491676	predicted	DarkChem Lite v0.1.0

Targets

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Details1. Mineralocorticoid receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Antagonist

General Function

Zinc ion binding

Specific Function

Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates targ...

Gene Name

NR3C2

Uniprot ID

P08235

Uniprot Name

Mineralocorticoid receptor

Molecular Weight

107066.575 Da

References

1. Trujillo H, Caravaca-Fontan F, Caro J, Morales E, Praga M: The Forgotten Antiproteinuric Properties of Diuretics. Am J Nephrol. 2021 Jul 7:1-15. doi: 10.1159/000517020. [Article]
2. FDA Approved Drug Products: Kerendia (Finerenone) Oral Tablet [Link]

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Drug created at December 15, 2020 18:14 / Updated at April 10, 2022 18:50