Study on the bioequivalence of two formulations of eplerenone in healthy volunteers under fasting conditions: data from a single-center, randomized, single-dose, open-label, 2-way crossover bioequivalence study

Abstract

Background: Eplerenone (CAS 107724-20-9) prevents the binding of aldosterone, a key hormone in the renin-angiotensin-aldosterone-system (RAAS), which is involved in the regulation of blood pressure and the pathophysiology of cardiovascular disease and is indicated, in addition to standard therapy including beta-blockers, to reduce the risk of cardiovascular mortality and morbidity in stable patients with left ventricular dysfunction (LVEF ≤ 40%) and clinical evidence of heart failure after recent myocardial infarction.

Objective: The aim of this study was to assess the bioequivalence of a new eplerenone 50 mg formulation (test formulation) vs. the reference product, as required by European regulatory authorities for the marketing of a generic product

Methods: This was a single-center, randomized, single-dose, open-label, 2-way crossover study in healthy volunteers under fasting conditions.

Plasma samples were collected up to 24 h post-dosing and plasma eplerenone levels were determined by reversed phase high performance liquid chromatography and by tandem mass spectrometry detection (ie, the LC-MS/MS method). Pharmacokinetic parameters were calculated using non-compartmental analysis.

Area under the concentration-time curve from time zero to time of last nonzero concentration (AUC_last) and maximum observed concentration (C_max) were the main evaluation criteria. All of the above-mentioned pharmacokinetic parameters were analyzed using 90% geometric confidence interval of the ratio (T/R) of least-squares means from the ANOVA of the In-transformed parameter. Tolerability was monitored using physical examination, including vital sign measurements and laboratory analysis.

Results: According to the classical approach, the 90% geometric confidence intervals obtained by analysis of variance for AUC_last and C_max were within the predefined ranges (80.00–125.00%).

Conclusion: Bioequivalence between test and reference formulations, both in terms of rate and extension of absorption, under fasting conditions was concluded according to European guidelines. Both formulations were well tolerated.

Key words

Aldosterone antagonist - Bioequivalence - Eplerenone - Gender - Generic

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