Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone - results from first-in-man and relative bioavailability studies

Fundamental and Clinical Pharmacology

Volumn 30, Issue 2, 2016, Pages 172-184

  Lentini, Silvia ^a   Heinig, Roland ^a   Kimmeskamp Kirschbaum, Nina ^a   Wensing, Georg ^a  

^a BAYER PHARMA AG   (Germany)

Author keywords

Finerenone; Mineralocorticoid receptor antagonist; Pharmacokinetics; Safety; Tolerability

Indexed keywords

ALDOSTERONE; ANGIOTENSIN II; CALCIUM; FINERENONE; MACROGOL; MAGNESIUM; NORADRENALIN; PLACEBO; POTASSIUM; RENIN; SODIUM; MINERALOCORTICOID ANTAGONIST; NAPHTHYRIDINE DERIVATIVE; SOLUTION AND SOLUBILITY; TABLET;

ADULT; ALDOSTERONE BLOOD LEVEL; ANGIOTENSIN BLOOD LEVEL; APPLICATION SITE ERYTHEMA; AREA UNDER THE CURVE; ARTICLE; BACKACHE; CALCIUM URINE LEVEL; CONTROLLED STUDY; CROSSOVER PROCEDURE; DIARRHEA; DIZZINESS; DOSE RESPONSE; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG RELEASE; DRUG SAFETY; DRUG TOLERABILITY; DRUG TOLERANCE; ELECTROLYTE BLOOD LEVEL; ELIMINATION HALF-LIFE; FATIGUE; FIRST IN HUMAN STUDY; FLUSHING; GEOMETRY; HUMAN; HUMAN EXPERIMENT; LIMIT OF QUANTITATION; MAGNESIUM URINE LEVEL; MALE; MAXIMUM PLASMA CONCENTRATION; NORADRENALIN BLOOD LEVEL; NORMAL HUMAN; OPEN STUDY; OROPHARYNX PAIN; ORTHOSTATIC HYPOTENSION; PARALLEL DESIGN; PARESTHESIA; PLASMA RENIN ACTIVITY; POSTINFLAMMATORY HYPERPIGMENTATION; POTASSIUM URINE LEVEL; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RENAL CLEARANCE; RHINOPHARYNGITIS; SIDE EFFECT; SINGLE BLIND PROCEDURE; SINGLE DRUG DOSE; SODIUM URINE LEVEL; SUPRAVENTRICULAR TACHYCARDIA; TABLET; THROMBOPHLEBITIS; TIME TO MAXIMUM PLASMA CONCENTRATION; URINARY EXCRETION; ADVERSE EFFECTS; BIOAVAILABILITY; DIET RESTRICTION; EATING; FOOD DRUG INTERACTION; HALF LIFE TIME; MIDDLE AGED; ORAL DRUG ADMINISTRATION; PHARMACOKINETICS; PHYSIOLOGY; SOLUTION AND SOLUBILITY; THERAPEUTIC USE; YOUNG ADULT;

ADMINISTRATION, ORAL; ADULT; AREA UNDER CURVE; BIOLOGICAL AVAILABILITY; CROSS-OVER STUDIES; EATING; FASTING; FOOD-DRUG INTERACTIONS; HALF-LIFE; HUMANS; MALE; MIDDLE AGED; MINERALOCORTICOID RECEPTOR ANTAGONISTS; NAPHTHYRIDINES; PHARMACEUTICAL SOLUTIONS; TABLETS; YOUNG ADULT;

EID: 84959511270     PISSN: 07673981     EISSN: 14728206     Source Type: Journal    
DOI: 10.1111/fcp.12170     Document Type: Article

References (33)

1. Mizuno Y., Yoshimura M., Yasue H. et al. Aldosterone production is activated in failing ventricle in humans. Circulation (2001) 103 72-77.
2. Zannad F. Aldosterone and heart failure. Eur. Heart J. (1995) 16(Suppl N) 98-102.
3. Swedberg K., Eneroth P., Kjekshus J., Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation (1990) 82 1730-1736.
4. Greene E.L., Kren S., Hostetter T.H. Role of aldosterone in the remnant kidney model in the rat. J. Clin. Invest. (1996) 98 1063-1068.
5. Rocha R., Funder J.W. The pathophysiology of aldosterone in the cardiovascular system. Ann. N. Y. Acad. Sci. (2002) 970 89-100.
6. Hollenberg N.K. Aldosterone in the development and progression of renal injury. Kidney Int. (2004) 66 1-9.
7. Naruse M., Tanabe A., Sato A. et al. Aldosterone breakthrough during angiotensin II receptor antagonist therapy in stroke-prone spontaneously hypertensive rats. Hypertension (2002) 40 28-33.
8. Sato A., Saruta T. Aldosterone breakthrough during angiotensin-converting enzyme inhibitor therapy. Am. J. Hypertens. (2003) 16 781-788.
9. Pitt B., Zannad F., Remme W.J. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N. Engl. J. Med. (1999) 341 709-717.
10. Pitt B., Remme W., Zannad F. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. (2003) 348 1309-1321.
11. Zannad F., McMurray J.J., Krum H. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. (2011) 364 11-21.
12. Navaneethan S.D., Nigwekar S.U., Sehgal A.R., Strippoli G.F. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst. Rev. (2009) doi: 10.1002/14651858.CD007004.pub2.
13. Bomback A.S., Kshirsagar A.V., Amamoo M.A., Klemmer P.J. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am. J. Kidney Dis. (2008) 51 199-211.
14. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013ACCF/AHA Guideline for the Management of Heart Failure. Available at: https://circ.ahajournals.org/content/128/16/e240.full.pdf+html Accessed: 14 October 2015.
15. National Institute of Health and Care Excellence. Chronic heart failure: Management of chronic heart failure in adults in primary and secondary care. Available at: http://www.nice.org.uk/guidance/cg108/chapter/1-recommendations#treating-heart-failure Accessed: 14 October 2015.
16. Albert N.M., Yancy C.W., Liang L. et al. Use of aldosterone antagonists in heart failure. JAMA (2009) 302 1658-1665.
17. Fonarow G.C., Yancy C.W., Albert N.M. et al. Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF. Circ. Heart Fail. (2008) 1 98-106.
18. Garthwaite S.M., McMahon E.G. The evolution of aldosterone antagonists. Mol. Cell. Endocrinol. (2004) 217 27-31.
19. Brown J.J., Davies D.L., Ferriss J.B. et al. Comparison of surgery and prolonged spironolactone therapy in patients with hypertension, aldosterone excess, and low plasma renin. Br. Med. J. (1972) 2 729-734.
20. Corvol P., Michaud A., Menard J., Freifeld M., Mahoudeau J. Antiandrogenic effect of spirolactones: mechanism of action. Endocrinology (1975) 97 52-58.
21. Karagiannis A., Tziomalos K., Kakafika A., Florentin M., Athyros V.G. Eplerenone relieves spironolactone-induced painful gynaecomastia in a patient with primary aldosteronism. Nephrol. Dial. Transplant. (2007) 22 293.
22. Kolkhof P., Borden S.A. Molecular pharmacology of the mineralocorticoid receptor: prospects for novel therapeutics. Mol. Cell. Endocrinol. (2012) 350 310-317.
23. 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 1385-1403.
24. Kolkhof P., Delbeck M., Kretschmer A. et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J. Cardiovasc. Pharmacol. (2014) 64 69-78.
25. 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 2453-2463.
26. Bakris G.L., Agarwal R., Chan J.C. et al. Effect of Finerenone on Albuminuria in Patients With Diabetic Nephropathy: A Randomized Clinical Trial. JAMA (2015) 314 884-894.
27. Pitt B., Anker S.D., Bohm M. et al. Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): a randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur. J. Heart Fail. (2015) 17 224-232.
28. European Medicines Agency. Pharmacokinetic Studies in Man. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003127.pdfAccessed: 13 October 2015.
29. Bavry A. Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure - ARTS-HF. Summary of a presentation given by Dr. Gerasimos Filippatos at the European Society of Cardiology Congress, London, August 31, 2015. Available at: http://www.acc.org/latest-in-cardiology/clinical-trials/2015/08/30/04/45/arts-hf#sthash.YAVz9ezP.dpufAccessed: 14 October 2015.
30. Basit A.W., Podczeck F., Newton J.M., Waddington W.A., Ell P.J., Lacey L.F. Influence of polyethylene glycol 400 on the gastrointestinal absorption of ranitidine. Pharm. Res. (2002) 19 1368-1374.
31. Liddle G.W. Sodium diuresis induced by steroidal antagonists of aldosterone. Science (1957) 126 1016-1018.
32. Ross E.J., Winternitz W.W. The effect of an aldosterone antagonist on the renal response to sodium restriction. Clin. Sci. (1961) 20 143-148.
33. Ross E.J. Human assay of electrolyte-active steroids and their antagonists. Clin. Sci. (1962) 23 197-202.