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

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 378.432
Monoisotopic: 378.169190584
Chemical Formula
C21H22N4O3
Synonyms
  • Finerenone
External IDs
  • BAY 94-8862
  • BAY-94-8862

Pharmacology

Indication

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

Pharmacology
Reduce drug development failure rates
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AMineralocorticoid receptor
antagonist
Humans
Absorption

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.1 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.1

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.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

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
Adverseeffects
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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
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
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.
DrugInteraction
AbametapirThe serum concentration of Finerenone can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Finerenone can be increased when combined with Abatacept.
AbirateroneThe serum concentration of Finerenone can be increased when it is combined with Abiraterone.
AcalabrutinibThe serum concentration of Finerenone can be increased when it is combined with Acalabrutinib.
AcebutololThe risk or severity of hyperkalemia can be increased when Acebutolol is combined with Finerenone.
AceclofenacThe risk or severity of hyperkalemia can be increased when Aceclofenac is combined with Finerenone.
AcemetacinThe risk or severity of hyperkalemia can be increased when Acemetacin is combined with Finerenone.
AcetaminophenThe serum concentration of Finerenone can be increased when it is combined with Acetaminophen.
AcetazolamideThe serum concentration of Finerenone can be increased when it is combined with Acetazolamide.
Acetylsalicylic acidThe risk or severity of hyperkalemia can be increased when Acetylsalicylic acid is combined with Finerenone.
Interactions
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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.

Products

Products2
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International/Other Brands
Kerendia (Bayer)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
KerendiaTablet, film coated20 mg/1OralBayer HealthCare Pharmaceuticals Inc.2021-07-09Not applicableUS flag
KerendiaTablet, film coated10 mg/1OralBayer HealthCare Pharmaceuticals Inc.2021-07-09Not applicableUS flag

Categories

Drug Categories
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]
ChemSpider
28669387
RxNav
2562811
ChEMBL
CHEMBL2181927
Wikipedia
Finerenone

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentChronic Kidney Disease (CKD)1
3CompletedTreatmentDiabetic Kidney Disease (DKD)1
3RecruitingTreatmentHeart Failure1
2CompletedTreatmentDiabetic Nephropathy2
2CompletedTreatmentHeart Failure3
2Not Yet RecruitingOtherChronic Kidney Disease (CKD) / Type 2 Diabetes Mellitus1
1CompletedNot AvailableHeart Failure1
1CompletedNot AvailablePharmacology, Clinical1
1CompletedBasic ScienceChronic Kidney Disease (CKD) / Worsening Chronic Heart Failure1
1CompletedBasic ScienceDiabetic Nephropathy / Worsening Chronic Heart Failure1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Tablet, film coatedOral10 mg/1
Tablet, film coatedOral20 mg/1
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.0354 mg/mLALOGPS
logP2.21ALOGPS
logP1.85ChemAxon
logS-4ALOGPS
pKa (Strongest Acidic)14.87ChemAxon
pKa (Strongest Basic)6.06ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area110.26 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity109.13 m3·mol-1ChemAxon
Polarizability39.66 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Heinig R, Gerisch M, Bairlein M, Nagelschmitz J, Loewen S: Results from Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Effect of Finerenone on the Pharmacokinetics of Comedications. Eur J Drug Metab Pharmacokinet. 2020 Aug;45(4):433-444. doi: 10.1007/s13318-020-00610-y. [Article]
  2. Heinig R, Gerisch M, Engelen A, Nagelschmitz J, Loewen S: Pharmacokinetics of the Novel, Selective, Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone in Healthy Volunteers: Results from an Absolute Bioavailability Study and Drug-Drug Interaction Studies In Vitro and In Vivo. Eur J Drug Metab Pharmacokinet. 2018 Dec;43(6):715-727. doi: 10.1007/s13318-018-0483-9. [Article]
  3. 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]
  4. FDA Approved Drug Products: Kerendia (Finerenone) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C8
Uniprot ID
P10632
Uniprot Name
Cytochrome P450 2C8
Molecular Weight
55824.275 Da
References
  1. Heinig R, Gerisch M, Bairlein M, Nagelschmitz J, Loewen S: Results from Drug-Drug Interaction Studies In Vitro and In Vivo Investigating the Effect of Finerenone on the Pharmacokinetics of Comedications. Eur J Drug Metab Pharmacokinet. 2020 Aug;45(4):433-444. doi: 10.1007/s13318-020-00610-y. [Article]
  2. Heinig R, Gerisch M, Engelen A, Nagelschmitz J, Loewen S: Pharmacokinetics of the Novel, Selective, Non-steroidal Mineralocorticoid Receptor Antagonist Finerenone in Healthy Volunteers: Results from an Absolute Bioavailability Study and Drug-Drug Interaction Studies In Vitro and In Vivo. Eur J Drug Metab Pharmacokinet. 2018 Dec;43(6):715-727. doi: 10.1007/s13318-018-0483-9. [Article]
  3. 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]
  4. FDA Approved Drug Products: Kerendia (Finerenone) Oral Tablet [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d 24-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A1
Uniprot ID
P04798
Uniprot Name
Cytochrome P450 1A1
Molecular Weight
58164.815 Da
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]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: Kerendia (Finerenone) Oral Tablet [Link]

Drug created on December 15, 2020 18:14 / Updated on July 16, 2021 20:52