Mechanism Of Action
Eplerenone binds to the mineralocorticoid receptor and
blocks the binding of aldosterone, a component of the
renin-angiotensin-aldosterone-system (RAAS). Aldosterone synthesis, which
occurs primarily in the adrenal gland, is modulated by multiple factors,
including angiotensin II and non-RAAS mediators such as adrenocorticotropic
hormone (ACTH) and potassium. Aldosterone binds to mineralocorticoid receptors
in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood
vessels, and brain) tissues and increases blood pressure through induction of
sodium reabsorption and possibly other mechanisms.
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 aldosterone circulating levels do not
overcome the effects of eplerenone.
Eplerenone selectively binds to human mineralocorticoid
receptors relative to its binding to recombinant human glucocorticoid,
progesterone, and androgen receptors.
There was no significant change in average heart rate
among patients treated with INSPRA in the combined clinical studies. No
consistent effects of INSPRA on heart rate, QRS duration, or PR or QT interval
were observed in 147 normal subjects evaluated for electrocardiographic changes
during pharmacokinetic studies.
Eplerenone is cleared predominantly by cytochrome P450
(CYP) 3A4 metabolism, with an elimination half-life of 3 to 6 hours. Steady
state is reached within 2 days. Absorption is not affected by food. Inhibitors
of CYP3A (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone.
Absorption And Distribution
Mean peak plasma concentrations of eplerenone are reached
approximately 1.5 to 2 hours following oral administration. Absorption is not
affected by food.The absolute bioavailability of eplerenone is 69% following
administration of a 100 mg oral tablet. Both peak plasma levels (Cmax) and area
under the curve (AUC) are dose proportional for doses of 25 mg to 100 mg and
less than proportional at doses above 100 mg. Upon repeat dosing, steady state
levels are reached within 2 days.
The plasma protein binding of eplerenone is about 50% and
it is primarily bound to alpha 1-acid glycoproteins. The apparent volume of
distribution at steady state ranged from 42 to 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.
Age, Gender, And Race
The pharmacokinetics of eplerenone at a dose of 100 mg
once daily has been investigated in the elderly (≥65 years), in males and
females, and in Blacks. At steady state, elderly subjects had increases in Cmax
(22%) and AUC (45%) compared with younger subjects (18 to 45 years). The
pharmacokinetics of eplerenone did not differ significantly between males and
females. At steady state, Cmax was 19% lower and AUC was 26% lower in Blacks [see
DOSAGE AND ADMINISTRATION and Use In Specific Populations].
The pharmacokinetics of eplerenone was evaluated in
patients with varying degrees of renal impairment 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 WARNINGS AND PRECAUTIONS].
The pharmacokinetics of eplerenone 400 mg has 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.
The pharmacokinetics of eplerenone 50 mg was evaluated in
8 patients with heart failure (NYHA classification II–IV) and 8 matched
(gender, age, weight) healthy controls. Compared with the controls, steady
state AUC and Cmax in patients with stable heart failure were 38% and 30%
Eplerenone is metabolized primarily by CYP3A4. Inhibitors
of CYP3A cause increased exposure [see DRUG INTERACTIONS].
Drug-drug interaction studies were conducted with a 100
mg dose of eplerenone.
Following a single dose of INSPRA 100 mg and CYP3A
inhibitor ketoconazole 200 mg twice a day, eplerone's Cmax was 1.7-fold and AUC
was 5.4-fold compared with eplerone alone.
Administration of eplerenone with moderate CYP3A inhibitors
(e.g., erythromycin 500 mg BID, verapamil 240 mg once daily, saquinavir 1200 mg
three times a day, fluconazole 200 mg once daily) resulted in increases in Cmax
of eplerenone ranging from 40% to 60% and AUC from 100% to 190%.
Grapefruit juice caused a 25% increase in exposure.
Eplerenone is not an inhibitor of CYP1A2, CYP3A4,
CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of
amiodarone, amlodipine, astemizole, chlorzoxazone, cisapride, dexamethasone,
dextromethorphan, diclofenac, 17α-ethinyl estradiol, fluoxetine, losartan,
lovastatin, mephobarbital, methylphenidate, methylprednisolone, metoprolol,
midazolam, nifedipine, phenacetin, phenytoin, simvastatin, tolbutamide,
triazolam, verapamil, or warfarin in vitro. Eplerenone is not a substrate or an
inhibitor of P-Glycoprotein at clinically relevant doses.
No clinically significant drug-drug pharmacokinetic
interactions were observed when eplerenone was administered with cisapride,
cyclosporine, digoxin, glyburide, midazolam, oral contraceptives
(norethindrone/ethinyl estradiol), simvastatin, or warfarin. St. John's wort (a
CYP3A inducer) caused a small (about 30%) decrease in eplerenone AUC.
No significant changes in eplerenone pharmacokinetics
were observed when eplerenone was administered with aluminum-and
Heart Failure Post-Myocardial Infarction
The eplerenone post-acute myocardial infarction heart
failure efficacy and survival study (EPHESUS) was a multinational, multicenter,
double-blind, randomized, placebo-controlled study in patients clinically
stable 3 to 14 days after an acute MI with LV dysfunction (as measured by left
ventricular ejection fraction [LVEF] ≤40%) and either diabetes or
clinical evidence of HF (pulmonary congestion by exam or chest x-ray or S3).
Patients with HF of valvular or congenital etiology, patients with unstable
post-infarct angina, and patients with serum potassium >5.0 mEq/L or serum
creatinine >2.5 mg/dL were to be excluded. Patients were allowed to receive
standard post-MI drug therapy and to undergo revascularization by angioplasty
or coronary artery bypass graft surgery.
Patients randomized to INSPRA were given 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 mEq/L. Dosage was reduced or suspended
anytime during the study if serum potassium levels were ≥5.5 mEq/L [see DOSAGE
EPHESUS randomized 6,632 patients (9.3% U.S.) at 671
centers in 27 countries. The study population was primarily white (90%, with 1%
Black, 1% Asian, 6% Hispanic, 2% other) and male (71%). The mean age was 64
years (range, 22 to 94 years). The majority of patients had pulmonary
congestion (75%) by exam or x-ray and were Killip Class II (64%). The mean
ejection fraction was 33%. The average time to enrollment was 7 days post-MI.
Medical histories prior to the index MI included hypertension (60%), coronary
artery disease (62%), dyslipidemia (48%), angina (41%), type 2 diabetes (30%),
previous MI (27%), and HF (15%).
The mean dose of INSPRA was 43 mg/day. Patients also
received standard care including aspirin (92%), ACE inhibitors (90%),
beta-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase
Patients were followed for an average of 16 months
(range, 0 to 33 months). The ascertainment rate for vital status was 99.7%.
The co-primary endpoints for EPHESUS were (1) the time to
death from any cause, and (2) the time to first occurrence of either
cardiovascular mortality [defined as sudden cardiac death or death due to
progression of HF, stroke, or other CV causes] or CV hospitalization (defined
as hospitalization for progression of HF, ventricular arrhythmias, acute MI, or
For the co-primary endpoint for death from any cause,
there were 478 deaths in the INSPRA group (14.4%) and 554 deaths in the placebo
group (16.7%). The risk of death with INSPRA was reduced by 15% [hazard ratio
equal to 0.85 (95% confidence interval 0.75 to 0.96; p = 0.008 by log rank
test)]. Kaplan-Meier estimates of all-cause mortality are shown in Figure 1 and
the components of mortality are provided in Table 5.
Figure 1: Kaplan-Meier Estimates of All-Cause
Table 5: Components of All-Cause Mortality in EPHESUS
(N=3319) n (%)
(N=3313) n (%)
|Death from any cause
|Unknown or unwitnessed death
Most CV deaths were attributed to sudden death, acute MI,
The time to first event for the co-primary endpoint of CV
death or hospitalization, as defined above, was longer in the INSPRA group
(hazard ratio 0.87, 95% confidence interval 0.79 to 0.95, p = 0.002). An
analysis that included the time to first occurrence of CV mortality and all CV
hospitalizations (atrial arrhythmia, angina, CV procedures, progression of HF,
MI, stroke, ventricular arrhythmia, or other CV causes) showed a smaller effect
with a hazard ratio of 0.92 (95% confidence interval 0.86 to 0.99; p = 0.028).
The combined endpoints, including combined all-cause hospitalization and
mortality were driven primarily by CV mortality. The combined endpoints in
EPHESUS, including all-cause hospitalization and all-cause mortality, are
presented in Table 6.
Table 6: Rates of Death or Hospitalization in EPHESUS
|CV death or hospitalization for progression of HF, stroke, MI or ventricular arrhythmia1
|CV death or hospitalization for progression of HF, stroke, MI, ventricular arrhythmia, atrial arrhythmia, angina, CV procedures, or other CV causes (PVD; Hypotension)
|All-cause death or hospitalization
|1 Co-Primary Endpoint.
Mortality hazard ratios varied for some subgroups as
shown in Figure 2. Mortality hazard ratios appeared favorable for INSPRA for
both genders and for all races or ethnic groups, although the numbers of
non-Caucasians were low (648, 10%). Patients with diabetes without clinical
evidence of HF and patients greater than 75 years did not appear to benefit
from the use of INSPRA. Such subgroup analyses must be interpreted cautiously.
Figure 2: Hazard Ratios of All-Cause Mortality by
Analyses conducted for a variety of CV biomarkers did not
confirm a mechanism of action by which mortality was reduced.
The safety and efficacy of INSPRA have been evaluated
alone and in combination with other antihypertensive agents in clinical studies
of 3091 hypertensive patients. The studies included 46% women, 14% Blacks, and
22% elderly (age ≥65). The studies excluded patients with elevated
baseline serum potassium (>5.0 mEq/L) and elevated baseline serum creatinine
(generally >1.5 mg/dL in males and >1.3 mg/dL in females).
Two fixed-dose, placebo-controlled, 8-to 12-week
monotherapy studies in patients with baseline diastolic blood pressures of 95
to 114 mm Hg were conducted to assess the antihypertensive effect of INSPRA. In
these two studies, 611 patients were randomized to INSPRA and 140 patients to
placebo. Patients received INSPRA in doses of 25 mg to 400 mg daily as either a
single daily dose or divided into two daily doses. The mean placebo-subtracted
reductions in trough cuff blood pressure achieved by INSPRA in these studies at
doses up to 200 mg are shown in Figures 3 and 4.
Figure 3: INSPRA Dose Response - Trough Cuff SBP
Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies
Figure 4: INSPRA Dose Response - Trough Cuff DBP
Placebo-Subtracted Adjusted Mean Change from Baseline in Hypertension Studies
Patients treated with INSPRA 50 mg to 200 mg daily
experienced significant decreases in sitting systolic and diastolic blood
pressure at trough with differences from placebo of 6–13 mm Hg (systolic) and
3–7 mm Hg (diastolic). These effects were confirmed by assessments with 24-hour
ambulatory blood pressure monitoring (ABPM). In these studies, assessments of
24-hour ABPM data demonstrated that INSPRA, administered once or twice daily,
maintained antihypertensive efficacy over the entire dosing interval. However,
at a total daily dose of 100 mg, INSPRA administered as 50 mg twice per day
produced greater trough cuff (4/3 mm Hg) and ABPM (2/1 mm Hg) blood pressure
reductions than 100 mg given once daily.
Blood pressure lowering was apparent within 2 weeks from
the start of therapy with INSPRA, with maximal antihypertensive effects
achieved within 4 weeks. Stopping INSPRA following treatment for 8 to 24 weeks
in six studies did not lead to adverse event rates in the week following
withdrawal of INSPRA greater than following placebo or active control
withdrawal. Blood pressures in patients not taking other antihypertensives rose
1 week after withdrawal of INSPRA by about 6/3 mm Hg, suggesting that the antihypertensive
effect of INSPRA was maintained through 8 to 24 weeks.
Blood pressure reductions with INSPRA in the two
fixed-dose monotherapy studies and other studies using titrated doses, as well
as concomitant treatments, were not significantly different when analyzed by
age, gender, or race with one exception. In a study in patients with low renin
hypertension, blood pressure reductions in Blacks were smaller than those in
whites during the initial titration period with INSPRA.
INSPRA has been studied concomitantly with treatment with
ACE inhibitors, ARB, calcium channel blockers, beta-blockers, and
hydrochlorothiazide. When administered concomitantly with one of these drugs
INSPRA usually produced its expected antihypertensive effects.