Generic placeholder image

Current Drug Discovery Technologies

Editor-in-Chief

ISSN (Print): 1570-1638
ISSN (Online): 1875-6220

Review Article

Finerenone: A Novel Drug Discovery for the Treatment of Chronic Kidney Disease

Author(s): Akshita Rana and Jagdish K. Sahu*

Volume 21, Issue 6, 2024

Published on: 26 January, 2024

Article ID: e290124226291 Pages: 9

DOI: 10.2174/0115701638283354240103115420

Price: $65

conference banner
Abstract

Background: The most common cause of chronic kidney disease (CKD) is diabetic nephropathy (DN). Primarilymineralocorticoid receptor antagonists (MRAs) (spironolactone and eplerenone), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used for the treatment of CKD, but due to the high risk of hyperkalaemia, the combination was infrequently used. Currently after approval by FDA in 2021, finerenone was found to be effective in the treatment of CKD. Finerenone slowdowns the progression of diabetic nephropathy and lessens the cardiovascular morbidity in DN patients.

Objective: The main objective of this review article is to provide a comprehensive and insightful overview of the role of finerenone by mainly focusing on its pharmacological properties, toxicity, uses, bioanalytical technique used for determination, and treatment options.

Materials and Method: Finerenone works by inhibiting the action of the mineralocorticoid receptor. Finerenone is quickly absorbed from the digestive tract after oral treatment and achieves peak plasma concentrations in 1-2 hours.

Result: Finerenone is actively metabolized through oxidation, epoxidation substitution, and direct hydroxylation. Elimination of finerenone is done through urine and feces. Determination of finerenone can be done through HPLC-MS and LSC.

Conclusion: The present review covers the complete picture of ADME properties, bioanalytical techniques, clinical trials, toxicity, and possible avenues in this arena. Finerenone is effective compared to other mineralocorticoid receptor-like spironolactone and eplerenone, for the treatment of chronic kidney disease.

Keywords: Chronic kidney diseases, finerenone, bioanalytical technique, metabolic pathway, hyperkalemia, diabetic nephropathy.

Graphical Abstract
[1]
Veneti S, Tziomalos K. The role of finerenone in the management of diabetic nephropathy. Diabetes Ther 2021; 12(7): 1791-7.
[http://dx.doi.org/10.1007/s13300-021-01085-z] [PMID: 34050896]
[2]
Goyal A, Gupta Y, Singla R, Kalra S, Tandon N. American diabetes association standards of medical care—2020 for gestational diabetes mellitus: A critical appraisal. Diabetes Ther 2020; 11(8): 1639-44.
[http://dx.doi.org/10.1007/s13300-020-00865-3] [PMID: 32564336]
[3]
Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: Pathophysiological basis. Kidney Int 2019; 96(2): 302-19.
[http://dx.doi.org/10.1016/j.kint.2019.02.030] [PMID: 31133455]
[4]
Ruilope LM, Agarwal R, Chan JC, et al. Rationale, design, and baseline characteristics of ARTS-DN: A randomized study to assess the safety and efficacy of finerenone in patients with type 2 diabetes mellitus and a clinical diagnosis of diabetic nephropathy. Am J Nephrol 2014; 40(6): 572-81.
[http://dx.doi.org/10.1159/000371497] [PMID: 25591469]
[5]
Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation 2016; 134(10): 752-72.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021887] [PMID: 27470878]
[6]
Lentini S, Heinig R, Kimmeskamp-Kirschbaum N, Wensing G. Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone – results from first‐in‐man and relative bioavailability studies. Fundam Clin Pharmacol 2016; 30(2): 172-84.
[http://dx.doi.org/10.1111/fcp.12170] [PMID: 26604072]
[7]
Burnier M, Damianaki A. Hypertension as cardiovascular risk factor in chronic kidney disease. Circ Res 2023; 132(8): 1050-63.
[http://dx.doi.org/10.1161/CIRCRESAHA.122.321762]
[8]
Filippatos G, Anker SD, Böhm M, et al. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016; 37(27): 2105-14.
[http://dx.doi.org/10.1093/eurheartj/ehw132] [PMID: 27130705]
[9]
Fujii W, Shibata S. Mineralocorticoid receptor antagonists for preventing chronic kidney disease progression: current evidence and future challenges. Int J Mol Sci 2023; 24(9): 7719.
[http://dx.doi.org/10.3390/ijms24097719]
[10]
DeFilippis EM, Desai AS. Treatment of hyperkalemia in heart failure. Curr Heart Fail Rep 2017; 14(4): 266-74.
[http://dx.doi.org/10.1007/s11897-017-0341-0]
[11]
Sztechman D, Czarzasta K, Cudnoch-Jedrzejewska A, Szczepanska-Sadowska E, Zera T. Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries. J Physiol Pharmacol 2018; 69(6)
[http://dx.doi.org/10.26402/jpp.2018.6.01]
[12]
Kolkhof P, Bärfacker L. 30 years of the mineralocorticoid receptor: Mineralocorticoid receptor antagonists: 60 years of research and development. J Endocrinol 2017; 234(1): 125-40.
[http://dx.doi.org/10.1530/JOE-16-0600]
[13]
Ruilope LM, Agarwal R, Anker SD, et al. blood pressure and cardiorenal outcomes with finerenone in chronic kidney disease in type 2 diabetes. Hypertension 2022; 79(12): 2685-95.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.122.19744] [PMID: 36252131]
[14]
Filippatos G, Anker SD, Pitt B, et al. Finerenone and heart failure outcomes by kidney function/albuminuria in chronic kidney disease and diabetes. JACC Heart Fail 2022; 10(11): 860-70.
[http://dx.doi.org/10.1016/j.jchf.2022.07.013] [PMID: 36328655]
[15]
Filippatos G, Anker SD, Agarwal R, et al. Finerenone and cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. Circulation 2021; 143(6): 540-52.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051898] [PMID: 33198491]
[16]
Snelder N, Heinig R, Drenth HJ, et al. Population pharmacokinetic and exposure–response analysis of finerenone: insights based on phase iib data and simulations to support dose selection for pivotal trials in type 2 diabetes with chronic kidney disease. Clin Pharmacokinet 2020; 59(3): 359-70.
[http://dx.doi.org/10.1007/s40262-019-00820-x] [PMID: 31583611]
[17]
Naegele M, Hernandez AF, Ruschitzka F. Finerenone in heart failure: Walking a fine line. Eur Heart J 2016; 37(27): 2115-7.
[http://dx.doi.org/10.1093/eurheartj/ehw155]
[18]
Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013; 369(20): 1892-903.
[http://dx.doi.org/10.1056/NEJMoa1303154] [PMID: 24206457]
[19]
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; 43(6): 715-27.
[http://dx.doi.org/10.1007/s13318-018-0483-9] [PMID: 29779093]
[20]
Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J 2022; 43(6): 474-84.
[http://dx.doi.org/10.1093/eurheartj/ehab777] [PMID: 35023547]
[21]
Rico-Mesa JS, White A, Ahmadian-Tehrani A, Anderson AS. Mineralocorticoid receptor antagonists: A comprehensive review of finerenone. Curr Cardiol Rep 2020; 22(11): 140.
[http://dx.doi.org/10.1007/s11886-020-01399-7] [PMID: 32910349]
[22]
Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy. JAMA 2015; 314(9): 884-94.
[http://dx.doi.org/10.1001/jama.2015.10081] [PMID: 26325557]
[23]
Yang J, Young MJ. The mineralocorticoid receptor and its coregulators. J Mol Endocrinol 2009; 43(2): 53-64.
[http://dx.doi.org/10.1677/JME-09-0031] [PMID: 19617444]
[24]
Vodošek Hojs N, Bevc S, Ekart R, Piko N, Petreski T, Hojs R. Mineralocorticoid receptor antagonists in diabetic kidney disease. Pharmaceuticals 2021; 14(6): 561.
[http://dx.doi.org/10.3390/ph14060561]
[25]
Bello AK, Alrukhaimi M, Ashuntantang GE, et al. Complications of chronic kidney disease: Current state, knowledge gaps, and strategy for action. Kidney Int Suppl 2017; 7(2): 122-9.
[http://dx.doi.org/10.1016/j.kisu.2017.07.007]
[26]
Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med 2020; 383(23): 2219-29.
[http://dx.doi.org/10.1056/NEJMoa2025845] [PMID: 33264825]
[27]
Kolkhof P, Delbeck M, Kretschmer A, et al. Finerenone, a Novel Selective Nonsteroidal Mineralocorticoid Receptor Antagonist Protects From Rat Cardiorenal Injury 2014. Available from: www.jcvp.org
[http://dx.doi.org/10.1097/FJC.0000000000000091]
[28]
Sica DA. Mineralocorticoid receptor antagonists for treatment of hypertension and heart failure. Methodist DeBakey Cardiovasc J 2015; 11(4): 235-9.
[http://dx.doi.org/10.14797/mdcj-11-4-235] [PMID: 27057293]
[29]
Cicoira M, Zanolla L, Rossi A, et al. Failure of aldosterone suppression despite angiotensin-converting enzyme (ACE) inhibitor administration in chronic heart failure is associated with ACE DD genotype. J Am Coll Cardiol 2001; 37(7): 1808-12.
[http://dx.doi.org/10.1016/S0735-1097(01)01237-2] [PMID: 11401115]
[30]
Tsuda K. Renin-Angiotensin system and sympathetic neurotransmitter release in the central nervous system of hypertension. Int J Hypertens 2012; 2012: 1-11.
[http://dx.doi.org/10.1155/2012/474870] [PMID: 23227311]
[31]
Santos RAS, Oudit GY, Verano-Braga T, Canta G, Steckelings UM, Bader M. The renin-angiotensin system: Going beyond the classical paradigms. Am J Physiol Heart Circ Physiol 2019; 316(5): H958-70.
[http://dx.doi.org/10.1152/ajpheart.00723.2018] [PMID: 30707614]
[32]
Liu LCY, Schutte E, Gansevoort RT, van der Meer P, Voors AA. Finerenone: third-generation mineralocorticoid receptor antagonist for the treatment of heart failure and diabetic kidney disease. Expert Opin Investig Drugs 2015; 24(8): 1123-35.
[http://dx.doi.org/10.1517/13543784.2015.1059819] [PMID: 26095025]
[33]
Goulooze SC, Heerspink HJL, van Noort M, et al. Dose–exposure–response analysis of the nonsteroidal mineralocorticoid receptor antagonist finerenone on uacr and egfr: an analysis from fidelio-dkd. Clin Pharmacokinet 2022; 61(7): 1013-25.
[http://dx.doi.org/10.1007/s40262-022-01124-3] [PMID: 35508594]
[34]
Jamsen KM, McLeay SC, Barras MA, Green B. Reporting a population pharmacokinetic-pharmacodynamic study: A journal’s perspective. Clin Pharmacokinet 2014; 53(2): 111-22.
[http://dx.doi.org/10.1007/s40262-013-0114-1] [PMID: 24327237]
[35]
Li Z, Zhao H, Wang J. Metabolism and chronic inflammation: The links between chronic heart failure and comorbidities. Front Cardiovasc Med 2021; 8: 650278.
[http://dx.doi.org/10.3389/fcvm.2021.650278] [PMID: 34026868]
[36]
Kalantar-Zadeh K, Jafar TH, Nitsch D, Neuen BL, Perkovic V. Chronic kidney disease. The Lancet 2021; 786-802.
[http://dx.doi.org/10.1016/S0140-6736(21)00519-5]
[37]
Filippatos G, Bakris GL, Pitt B, et al. Finerenone reduces new-onset atrial fibrillation in patients with chronic kidney disease and type 2 diabetes. J Am Coll Cardiol 2021; 78(2): 142-52.
[http://dx.doi.org/10.1016/j.jacc.2021.04.079] [PMID: 34015478]
[38]
Rossing P, Filippatos G, Agarwal R, et al. Finerenone in predominantly advanced ckd and type 2 diabetes with or without sodium-glucose cotransporter-2 inhibitor therapy. Kidney Int Rep 2022; 7(1): 36-45.
[http://dx.doi.org/10.1016/j.ekir.2021.10.008] [PMID: 35005312]
[39]
Heinig R, Nagelschmitz J, Loewen S. Results from phase i studies investigating the dose linearity of finerenone tablets and the influence of food or ph-modifying comedications on its pharmacokinetics in healthy male volunteers. Eur J Drug Metab Pharmacokinet 2022; 47(4): 549-59.
[http://dx.doi.org/10.1007/s13318-022-00770-z] [PMID: 35612708]
[40]
Gerisch M, Heinig R, Engelen A, et al. Biotransformation of finerenone, a novel nonsteroidal mineralocorticoid receptor antagonist, in dogs, rats, and humans, in vivo and in vitro. Drug Metab Dispos 2018; 46(11): 1546-55.
[http://dx.doi.org/10.1124/dmd.118.083337] [PMID: 30171161]
[41]
Carrero JJ, Grams ME, Sang Y, et al. Albuminuria changes are associated with subsequent risk of end-stage renal disease and mortality. Kidney Int 2017; 91(1): 244-51.
[http://dx.doi.org/10.1016/j.kint.2016.09.037] [PMID: 27927597]
[42]
Zhang MZ, Bao W, Zheng QY, Wang YH, Sun LY. Efficacy and safety of finerenone in chronic kidney disease: A systematic review and meta-analysis of randomized clinical trials. Front Pharmacol 2022; 13: 819327.
[http://dx.doi.org/10.3389/fphar.2022.819327]
[43]
Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, double-blind trial. Eur Heart J 2013; 34(31): 2453-63.
[http://dx.doi.org/10.1093/eurheartj/eht187] [PMID: 23713082]
[44]
Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GFM. Aldosterone antagonists for preventing the progression of chronic kidney disease: A systematic review and meta-analysis. Clin J Am Soc Nephrol 2009; 4(3): 542-51.
[http://dx.doi.org/10.2215/CJN.04750908] [PMID: 19261819]
[45]
Heinig R, Fricke R, Wertz S, Nagelschmitz J, Loewen S. Results from drug–drug interaction studies in vitro and in vivo investigating the inhibitory effect of finerenone on the drug transporters BCRP, OATP1B1, and OATP1B3. Eur J Drug Metab Pharmacokinet 2022; 47(6): 803-15.
[http://dx.doi.org/10.1007/s13318-022-00794-5] [PMID: 36029368]
[46]
Rossing P, Agarwal R, Anker SD, et al. Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by GLP‐1RA treatment: A subgroup analysis from the FIDELIO‐DKD trial. Diabetes Obes Metab 2022; 24(1): 125-34.
[http://dx.doi.org/10.1111/dom.14558] [PMID: 34580995]
[47]
Rohde G, Loewen S, Heinig R. Determination of finerenone – a novel, selective, nonsteroidal mineralocorticoid receptor antagonist – in human plasma by high-performance liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study in venous and capillary human plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2021; 1172: 122643.
[http://dx.doi.org/10.1016/j.jchromb.2021.122643] [PMID: 33770684]
[48]
Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of BAY 94-8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. ChemMedChem 2012; 7(8): 1385-403.
[http://dx.doi.org/10.1002/cmdc.201200081] [PMID: 22791416]
[49]
Zheng Y, Ma S, Huang Q, et al. Meta-analysis of the efficacy and safety of finerenone in diabetic kidney disease. Kidney Blood Press Res 2022; 47(4): 219-28.
[http://dx.doi.org/10.1159/000521908] [PMID: 35034019]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy