Exploring The Clinical Pharmacokinetics of Eplerenone: A Systematic Review of Published Studies
Main Article Content
Keywords
Eplerenone, aldosterone blocker, Pharmacokinetics, PK parameters, Systematic review
Abstract
Eplerenone is the first selective aldosterone antagonist to manage hypertension and congestive heart failure. This comprehensive review aims to collate all the published pharmacokinetic (PK) data on eplerenone by scavenging the relevant articles following oral route of administration in human subjects (healthy & diseased). Five databases, Science Direct, Cochrane Library, EBSCO, Google Scholar, and PubMed, were used systematically to retrieve the relevant studies containing at least one reported PK parameter of eplerenone. A total of 983 articles were identified, in which 08 studies were included after applying the inclusion/exclusion criteria. Eplerenone shows the linear PK profile as the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) increase dose-dependently. The Cmax was found to be increased by 2-fold following the administration of multiple doses in healthy as well as in subjects with renal impairment in comparison with single dose. In dialysis subjects, the peak time (Tmax) was significantly shorter than that of the healthy population, 1.28 ± 0.47 hr vs. 2.22 ± 0.75 hr. A significant increase in oral clearance (CL/F) was observed in dialysis patients compared to normal subjects after giving multiple doses. Moreover, co-administration of ketoconazole with eplerenone showed a 1.7-fold increase in Cmax. The current systematic review summarizes all the available PK parameters of eplerenone from the possible accessible studies that can assist clinicians in dosage adjustments in patients with renal failure and avoiding drug-drug interactions.
References
2. Muldowney III JA, Schoenhard JA, Benge CD. The clinical pharmacology of eplerenone. Expert Opin Drug Metab Toxicol.
2009;5(4):425-32.
3. Hughes JC, Cassagnol M. Eplerenone. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.
4. Sathukumati A, Potnuri N, Sharma J. Solubility and dissolution enhancement of eplerenone by using nanoprecipitation
technique. Asian J Sci Technol. 2020;11(12):11360-7.
5. McGraw J, Cherney M, Bichler K, Gerhardt A, Nauman M. The relative role of CYP3A4 and CYP3A5 in eplerenone metabolism.
Toxicol Lett. 2019;315:9-13.
6. Croom KF, Perry CM. Eplerenone. Am J Cardiovasc Drugs. 2005;5(1):51-69.
7. Seferovic PM, Pelliccia F, Zivkovic I, et al. Mineralocorticoid receptor antagonists, a class beyond spironolactone—Focus on the special pharmacologic properties of eplerenone. Int J Cardiol. 2015 Dec 1;200:3-7.
8. Khames A. Formulation and characterization of eplerenone nanoemulsion liquisolids, an oral delivery system with higher
release rate and improved bioavailability. Pharmaceutics. 2019;11(1):40.
9. Tam TS, Wu MH, Masson SC, et al. Eplerenone for hypertension. Cochrane Database Syst Rev. 2017;(2).
10. Eschalier R, McMurray JJ, Swedberg K, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: analyses of the EMPHASIS-HF study subgroups. J Am Coll Cardiol. 2013;62(17):1585-93.
11. Pelliccia F, Patti G, Rosano G, Greco C, Gaudio C. Efficacy and safety of eplerenone in the management of mild to moderate
arterial hypertension: systematic review and meta-analysis. Int J Cardiol. 2014 Nov 15;177(1):219-28.
12. Mobaraki H, Azami-Aghdash S, Sarabi Asiabar A, Rezapour A, Kafaei Mehr MH, Emamgolizadeh S. Cost-effectiveness of
eplerenone in treatment of cardiovascular diseases: a systematic review. Med J Islam Repub Iran. 2017;31:4.
13. Korol S, Mottet F, Perreault S, Baker WL, White M, de Denus S. A systematic review and meta-analysis of the impact of
mineralocorticoid receptor antagonists on glucose homeostasis. Medicine (Baltimore). 2017 Dec;96(48):e8719.
14. Frankenstein L, Seide S, Täger T, et al. Relative Efficacy of Spironolactone, Eplerenone, and cAnRenone in patients with Chronic Heart failure (RESEARCH): a systematic review and network meta-analysis of randomized controlled trials. Heart Fail Rev. 2020 Mar;25(2):161-71.
15. Felipe CQ, Biancardi AL, Civile VT, Carvas Junior N, Serracarbassa PD, Koike MK. Mineralocorticoid receptor antagonists for
chronic central serous chorioretinopathy: systematic review and meta-analyses. Int J Retina Vitreous. 2022 Jun 7;8(1):34.
16. McKenna C, Burch J, Suekarran S, et al. A systematic review and economic evaluation of the clinical effectiveness and costeffectiveness of aldosterone antagonists for postmyocardial infarction heart failure. Health Technol Assess. 2010 May;14(24):1-162.
17. Higgins J. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane
Collaboration. 2011. Available from: www.cochrane-handbook.org.
18. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264-9.
19. Rubin K, Sullivan D, Sadhasivam S. Are peripheral and neuraxial blocks with ultrasound guidance more effective and safe in
children? Paediatr Anaesth. 2009;19(2):92-6.
20. Long HA, French DP, Brooks JM. Optimising the value of the critical appraisal skills programme (CASP) tool for quality appraisal in qualitative evidence synthesis. Res Methods Med Health Sci. 2020;1(1):31-42.
21. Soliman ABE, Pawluk SA, Wilby KJ, Rachid O. The use of a modified Delphi technique to develop a critical appraisal tool for
clinical pharmacokinetic studies. Int J Clin Pharm. 2022;1-10. 22. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343.
23. Tawfik GM, Dila KAS, Mohamed MYF, et al. A step-by-step guide for conducting a systematic review and meta-analysis with
simulation data. Trop Med Health. 2019;47(1):1-9.
24. Chen J, Jiang B, Lou H, Xu Y, Shao R, Ruan Z. Dose proportionality and pharmacokinetics of eplerenone in healthy Chinese
subjects. Drug Res. 2016;66(3):154-9.
25. Almeida S, Pedroso P, Filipe A, et al. Study on the bioequivalence of two formulations of eplerenone in healthy volunteers
under fasting conditions. Arzneimittelforschung. 2011;61(3):153-9.
26. Zhang JY, Fast DM, Breau AP. Development and validation of a liquid chromatography–tandem mass spectrometric assay for eplerenone and its hydrolyzed metabolite in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;787(2):333-44.
27. Mori Y, Chiba K, Takahashi H, Ogata H. A population approach to eplerenone pharmacokinetics and saturable protein binding. Drug Metab Pharmacokinet. 2010;25(4):371-7.
28. Cook CS, Berry LM, Bible RH, Hribar JD, Hajdu E, Liu NW. Pharmacokinetics and metabolism of [14C] eplerenone after oral
administration to humans. Drug Metab Dispos. 2003;31(11):1448-55.
29. Thorstensen CW, Clasen PE, Rognstad S, et al. Development of UHPLC-MS/MS methods to quantify 25 antihypertensive drugs in serum in a cohort of patients treated for hypertension. J Pharm Biomed Anal. 2022;219:114908.
30. Ravis WR, Reid S, Sica DA, Tolbert DS. Pharmacokinetics of eplerenone after single and multiple dosing in subjects with and
without renal impairment. J Clin Pharmacol. 2005;45(7):810-21.
31. Cook C, Berry L, Burton E. Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition
data. Xenobiotica. 2004;34(3):215-28.
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.