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 recombinant human mineralocorticoid receptors relative to its
binding to recombinant human glucocorticoid, progesterone, and androgen receptors.
Pharmacokinetics
Eplerenone is cleared predominantly by cytochrome P450 (CYP) 3A4 metabolism, with an elimination
half-life of 4 to 6 hours. Steady state is reached within 2 days. Absorption is not affected by
food. Inhibitors of CYP3A4 (e.g., ketoconazole, saquinavir) increase blood levels of eplerenone.
Absorption and Distribution
Mean peak plasma concentrations of eplerenone are reached approximately 1.5 hours following oral
administration. 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 to 100 mg and less than proportional at doses above 100 mg.
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 43 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 4 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.]
Renal Impairment
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.]
Hepatic Impairment
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.
Heart Failure
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% higher, respectively.
Drug-Drug Interactions [See DRUG INTERACTIONS.]
Eplerenone is metabolized primarily by CYP3A4. Inhibitors of CYP3A4 cause increased exposure [see DRUG INTERACTIONS].
Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.
A pharmacokinetic study evaluating the administration of a single dose of INSPRA 100 mg with
ketoconazole 200 mg two times a day, a strong inhibitor of the CYP3A4 pathway, showed a 1.7-fold
increase in Cmax of eplerenone and a 5.4-fold increase in AUC of eplerenone.
Administration of eplerenone with moderate CYP3A4 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 1.4- to 1.6-fold and AUC from 2.0- to
2.9-fold.
Grapefruit juice caused only a small increase (about 25%) 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,
and 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 CYP3A4 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 magnesium-containing antacids.
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
Eplerenone was non-genotoxic in a battery of assays including in vitro bacterial mutagenesis
(Ames test in Salmonella spp. and E. Coli), in vitro mammalian cell mutagenesis
(mouse lymphoma cells), in vitro chromosomal aberration (Chinese hamster ovary cells), in vivo rat
bone marrow micronucleus formation, and in vivo/ex vivo unscheduled DNA synthesis in rat liver.
There was no drug-related tumor response in heterozygous P53 deficient mice when tested for
6 months at dosages up to 1000 mg/kg/day (systemic AUC exposures up to 9 times the exposure in
humans receiving the 100 mg/day therapeutic dose). Statistically significant increases in
benign thyroid tumors were observed after 2 years in both male and female rats when administered
eplerenone 250 mg/kg/day (highest dose tested) and in male rats only at 75 mg/kg/day.
These dosages provided systemic AUC exposures approximately 2 to 12 times higher than the
average human therapeutic exposure at 100 mg/day. Repeat dose administration of eplerenone
to rats increases the hepatic conjugation and clearance of thyroxin, which results in increased
levels of TSH by a compensatory mechanism. Drugs that have produced thyroid tumors by this
rodent-specific mechanism have not shown a similar effect in humans.
Male rats treated with eplerenone at 1000 mg/kg/day for 10 weeks (AUC 17 times that at the 100 mg/day human therapeutic dose)
had decreased weights of seminal vesicles and epididymides and slightly decreased fertility.
Dogs administered eplerenone at dosages of 15 mg/kg/day and higher (AUC 5 times that at the 100 mg/day human therapeutic dose)
had dose-related prostate atrophy. The prostate atrophy was reversible after daily treatment for 1 year at 100 mg/kg/day.
Dogs with prostate atrophy showed no decline in libido, sexual performance, or semen quality.
Testicular weight and histology were not affected by eplerenone in any test animal species at any dosage.