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Pharmacology: Pharmacodynamics: Mechanism of Action of Eplerenone: Eplerenone has relative selectivity in binding to recombinant human mineralocorticoid receptors compared to its binding to recombinant human glucocorticoid, progesterone and androgen receptors. Eplerenone 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.
Eplerenone has been shown to produce sustained increases in plasma renin and serum aldosterone, consistent with inhibition of the negative regulatory feedback of aldosterone on renin secretion. The resulting increased plasma renin activity and circulating aldosterone levels do not overcome the effects of eplerenone.
Heart Failure Post MI: In dose-ranging studies of chronic heart failure (NYHA classification II-IV), the addition of eplerenone to standard therapy resulted in expected dose-dependent increases in aldosterone.
Eplerenone was studied in EPHESUS, a double-blind, placebo-controlled study in 6632 subjects with acute MI, left ventricular dysfunction (as measured by LVEF ≤40%), and clinical signs of heart failure. Within 3 to 14 days (median 7 days) after an acute MI, patients received eplerenone or placebo in addition to standard therapies at an initial dose of 25 mg once daily and titrated to the target dose of 50 mg once daily after 4 weeks if serum potassium was <5.0 mmol/L. During the study, patients received standard care including acetylsalicylic acid (92%), ACE inhibitors (90%), beta blockers (83%), nitrates (72%), loop diuretics (66%), or HMG CoA reductase inhibitors (60%).
In EPHESUS, the co-primary endpoints were all-cause mortality and the combined endpoint of cardiovascular (CV) death or CV hospitalization; 14.4% of patients assigned to eplerenone and 16.7% of subjects assigned to placebo died (all causes), while 26.7% of patients assigned to eplerenone and 30.0% assigned to placebo met the combined endpoint of CV death or hospitalization. Thus, in EPHESUS, eplerenone reduced the risk of death from any cause by 15% (RR 0.85; 95% CI, 0.75-0.96; p = 0.008) compared to placebo, primarily by reducing CV mortality. The combined risk of CV death or CV hospitalization was reduced by 13% with eplerenone (RR 0.87; 95% CI, 0.79-0.95; p = 0.002). The absolute risk reductions for the endpoints all-cause mortality and combined CV mortality/hospitalization were 2.3% and 3.3%, respectively. Clinical efficacy was primarily demonstrated when eplerenone therapy was initiated in patients aged <75 years old. The benefits of therapy in those patients over the age of 75 are unclear. NYHA functional classification improved or remained stable for a statistically significant greater proportion of patients receiving eplerenone compared to placebo. The incidence of hyperkalemia was 3.4% in the eplerenone group vs. 2.0% in the placebo group (p < 0.001). The incidence of hypokalemia was 0.5% in the eplerenone group vs. 1.5% in the placebo group (p < 0.001).
Electrocardiography: No consistent effects of eplerenone on heart rate, QRS duration, or PR or QT interval were observed in 147 normal subjects evaluated for electrocardiographic changes during pharmacokinetic studies.
Pharmacokinetics: Absorption and Distribution: The absolute bioavailability of eplerenone is 69% following administration of a 100 mg oral tablet. Maximum plasma concentrations are reached after approximately 1.5 to 2 hours. Both peak plasma levels (Cmax) and area under the curve (AUC) are dose proportional for doses of 10 mg to 100 mg and less than proportional at doses above 100 mg. Steady-state is reached within 2 days. Absorption is not affected by food.
The plasma protein binding of eplerenone is about 50% and is primarily bound to alpha 1-acid glycoproteins. The apparent volume of distribution at steady-state is estimated to be 42-90 L. Eplerenone does not preferentially bind to red blood cells.
Metabolism and Excretion: Eplerenone metabolism is primarily mediated via CYP3A4. No active metabolites of eplerenone have been identified in human plasma.
Less than 5% of an eplerenone dose is recovered as unchanged drug in the urine and feces. Following a single oral dose of radiolabeled drug, approximately 32% of the dose was excreted in the feces and approximately 67% was excreted in the urine. The elimination half-life of eplerenone is approximately 3 to 6 hours. The apparent plasma clearance is approximately 10 L/hr.
Special Populations: Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (≥65 years), in males and females, and in blacks. The pharmacokinetics of eplerenone did not differ significantly between males and females. At steady-state, elderly subjects had increases in Cmax (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady-state, Cmax was 19% lower and AUC was 26% lower in blacks (see Dosage & Administration).
Renal Insufficiency: The pharmacokinetics of eplerenone were evaluated in patients with varying degrees of renal insufficiency and in patients undergoing hemodialysis. Compared with control subjects, steady-state AUC and Cmax were increased by 38% and 24%, respectively, in patients with severe renal impairment and were decreased by 26% and 3%, respectively, in patients undergoing hemodialysis. No correlation was observed between plasma clearance of eplerenone and creatinine clearance. Eplerenone is not removed by hemodialysis (see Overdosage).
Hepatic Insufficiency: The pharmacokinetics of eplerenone 400 mg have been investigated in patients with moderate (Child-Pugh Class B) hepatic impairment and compared with normal subjects. Steady-state Cmax and AUC of eplerenone were increased by 3.6% and 42%, respectively (see Dosage & Administration). Since the use of eplerenone has not been investigated in patients with severe hepatic impairment, eplerenone is contraindicated in this patient group (see Contraindications).
Heart Failure: The pharmacokinetics of eplerenone 50 mg were evaluated in patients with heart failure (NYHA classification II-IV). Compared with healthy subjects matched according to age, weight and gender, steady-state AUC and Cmax in heart failure patients were 38% and 30% higher, respectively. Consistent with these results, a population pharmacokinetic analysis of eplerenone based on a subset of patients from EPHESUS indicates that apparent clearance of eplerenone in patients with heart failure was similar to that in healthy elderly subjects.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Preclinical studies of safety pharmacology, genotoxicity, carcinogenic potential and reproductive toxicity revealed no special hazard for humans.
In repeated dose toxicity studies, prostate atrophy was observed in rats and dogs at exposure levels several-fold above clinical exposure levels. The prostatic changes were not associated with adverse functional consequences. The clinical relevance of these findings is unknown.
Studies in rats and rabbits showed no teratogenic effects, although decreased body weight in maternal rabbits and increased rabbit fetal resorptions and post-implantation loss were observed at the highest administered dosage.
