Inspra Mechanism of Action

Pharmacologic Category: Aldosterone Antagonist.
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.
Hypertension: Eplerenone was studied in 3091 hypertensive patients, comprising 46% women, 14% blacks and 22% ≥65 years. Patients were excluded if they had elevated baseline serum potassium (>5.0 mmol/L) or creatinine >133 μmol/L for men and >115 μmol/L for women. Two fixed-dose, placebo-controlled 8 to 12 week monotherapy studies in hypertensive patients randomized 611 patients to eplerenone (doses ranging from 25 mg to 400 mg daily as either a single daily dose or two daily doses) and 140 subjects to placebo. Patients treated with 50 mg to 200 mg daily experienced significant decreases in sitting blood pressure at trough with differences from placebo of 6-13 mmHg (systolic) and 3-7 mmHg (diastolic), effects confirmed with 24-hour ambulatory measurements.
Blood pressure lowering was apparent by 2 weeks and the maximal effect by 4 weeks of treatment. In 6 studies, after 8 to 24 weeks of therapy the discontinuation of eplerenone, placebo or active control resulted in similar adverse event rates in the week following withdrawal. In eplerenone-treated patients blood pressure rose in patients not taking other antihypertensives, suggesting that eplerenone's effect was maintained through 8 to 24 weeks. Overall, eplerenone's effects are unaffected by age, gender or race with the exception of patients with low renin hypertension where a single study showed smaller blood pressure reductions with eplerenone in black than white patients during the initial titration period.
Eplerenone has been studied concomitantly with treatment with ACE inhibitors, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs eplerenone usually produced its expected antihypertensive effects.
Pediatric Population: In a 10-week study of pediatric patients with hypertension (age range 4 to 16 years, n=304), eplerenone, at doses (from 25 mg up to 100 mg per day) that produced exposure similar to that in adults, did not lower blood pressure effectively. In this study and in a 1-year pediatric safety study in 149 patients (age range 5 to 17 years), the safety profile was similar to that of adults. Eplerenone has not been studied in hypertensive patients less than 4 years old because the study in older pediatric patients showed a lack of efficacy (see Dosage & Administration).
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).
NYHA Class II (chronic) Heart Failure: In the EMPHASI-HF trial the effect of eplerenone when added to standard therapy was investigated on clinical outcomes in patients with systolic heart failure and mild symptoms (NYHA functional class II).
Patients were included if they were at least 55 years old, had a LVEF ≤30%, or LVEF ≤35% in addition to QRS duration of ˃130 msec, and were either hospitalized for CV reasons 6 months prior to inclusion or had a plasma level of B-type natriuretic peptide (BNP) of at least 250 pg/mL or a plasma level of N-terminal pro-BNP of at least 500 pg/mL in men (750 pg/mL in women). Eplerenone was started at a dose of 25 mg once daily and was increased after 4 weeks to 50 mg once daily if the serum potassium level was ˂5.0 mmol/L. Alternatively, if the estimated glomerular filtration rate (GFR) was 30-49 mL/min/1.73 m², eplerenone was started at 25 mg on alternate days, and increased to 25 mg once daily.
In total, 2737 patients were randomized (double-blind) to treatment with eplerenone or placebo including baseline therapy of diuretics (85%), ACE inhibitors (78%), angiotensin II receptor blockers (19%), beta blockers (87%), anti thrombotic drugs (88%), lipid-lowering agents (63%), and digitalis glycosides (27%). The mean LVEF was ~26% and the mean QRS duration was ~122 msec. Most of the patients (83.4%) were previously hospitalized for CV reasons within 6 months of randomization, with around 50% of them due to heart failure. Around 20% of the patients had implantable defibrillators or cardiac resynchronization therapy.
The primary endpoint, death from cardiovascular causes or hospitalization for heart failure occurred in 249 (18.3%) patients in the eplerenone group and 356 (25.9%) patients in the placebo group (RR 0.63, 95% CI, 0.54-0.74; p˂0.001). The effect of eplerenone on the primary endpoint outcomes was consistent across all pre-specified subgroups.
The secondary endpoint of all-cause mortality was met by 171 (12.5%) patients in the eplerenone group and 213 (15.5%) patients in the placebo group (RR 0.76; 95% CI, 0.62-0.93; p=0.008). Death from CV causes was reported in 147 (10.8%) patients in the eplerenone group and 185 (13.5%) subjects in the placebo group (RR 0.76; 95% CI, 0.61-0.94; p=0.01).
During the study, hyperkalemia (serum potassium level ˃5.5 mmol/L) was reported in 158 (11.8%) patients in the eplerenone group and 96 (7.2%) subjects in the placebo group (p ˂ 0.001). Hypokalemia, defined as serum potassium level ˂4.0 mmol/L, was statistically lower with eplerenone when compared to placebo (38.9% for eplerenone compared to 48.4% for placebo, p ˂0.0001).
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 (C_max) 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 C_max (22%) and AUC (45%) compared with younger subjects (18 to 45 years). At steady-state, C_max 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 C_max 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 C_max 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 C_max 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.
Pediatric Population: A population pharmacokinetic model for eplerenone concentrations from two studies in 51 pediatric hypertensive patients of ages 4 to 16 years identified that patient body weight had a statistically significant effect on eplerenone volume of distribution but not on its clearance. Eplerenone volume of distribution and peak exposure in a heavier pediatric patient are predicted to be similar to that in an adult of similar body weight; in a lighter 45-kg patient, the volume of distribution is about 40% lower and the peak exposure is predicted to be higher than typical adults. Eplerenone treatment was initiated at 25 mg once daily in pediatric patients and increased to 25 mg twice daily after 2 weeks and eventually 50 mg twice daily, if clinically indicated; at these doses, the highest observed eplerenone concentration in pediatric subjects were not substantially higher than those in adults initiated at 50 mg once daily.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: Pre-clinical studies of safety pharmacology, genotoxicity, carcinogenic potential and toxicity to reproduction 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.