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Inspra Pharmacology, Pharmacokinetics, Studies, Metabolism - Eplerenone

Inspra Pharmacology, Pharmacokinetics, Studies, Metabolism - Eplerenone

CLINICAL PHARMACOLOGY

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

General: 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 unknown. Both peak plasma levels (C_max) 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.

Special Populations

Age, Gender, and Race: The pharmacokinetics of eplerenone at a dose of 100 mg once daily have been investigated in the elderly (³65 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 PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Geriatric Use and DOSAGE AND ADMINISTRATION, Hypertension.)

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 WARNINGS, Hyperkalemia in Patients Treated for Hypertension and PRECAUTIONS, Hyperkalemia in Patients Treated for Congestive Heart Failure Post-Myocardial Infarction and Congestive Heart Failure Post-Myocardial Infarction and Hypertension.)

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 AND ADMINISTRATION, Hypertension.)

Heart Failure: The pharmacokinetics of eplerenone 50 mg were 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 C_max in patients with stable heart failure were 38% and 30% higher, respectively.

Drug-Drug Interactions

(See PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions .)

Drug-drug interaction studies were conducted with a 100 mg dose of eplerenone.

Eplerenone is metabolized primarily by CYP3A4. A potent inhibitor of CYP3A4 (ketoconazole) caused increased exposure of about 5-fold while less potent CYP3A4 inhibitors (erythromycin, saquinavir, verapamil, and fluconazole) gave approximately 2- fold increases. Grapefruit juice caused only a small increase (about 25%) in exposure. (See PRECAUTIONS, Congestive Heart Failure Post-Myocardial Infarction and Hypertension, Drug Interactions and DOSAGE AND ADMINISTRATION, Hypertension.)

Eplerenone is not an inhibitor of CYP1A2, CYP3A4, CYP2C19, CYP2C9, or CYP2D6. Eplerenone did not inhibit the metabolism of chlorzoxazone, diclofenac, methylphenidate, losartan, amiodarone, dexamethasone, mephobarbital, phenytoin, phenacetin, dextromethorphan, metoprolol, tolbutamide, amlodipine, astemizole, cisapride, 17a-ethinyl estradiol, fluoxetine, lovastatin, methylprednisolone, midazolam, nifedipine, simvastatin, 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 digoxin, warfarin, midazolam, cisapride, cyclosporine, simvastatin, glyburide, or oral contraceptives (norethindrone/ethinyl estradiol). St. Johns 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.

CLINICAL STUDIES

Congestive Heart Failure Post-Myocardial Infarction

The eplerenone post-acute myocardial infarction heart failure efficacy and survival study

(EPHESUS) was a multinationa l, multicenter, double-blind, randomized, placebo-controlled study in patients clinically stable 3-14 days after an acute myocardial infarction (MI) with left ventricular dysfunction (as measured by left ventricular ejection fraction [LVEF] £40%) and either diabetes or clinical evidence of congestive heart failure (CHF) (pulmonary congestion by exam or chest x-ray or S₃). Patients with CHF 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 ³ 5.5 mEq/L. (See DOSAGE AND ADMINISTRATION, Congestive Heart Failure Post-Myocardial Infarction.)

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, 22-94 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%), ß-blockers (83%), nitrates (72%), loop diuretics (66%), or HMG-CoA reductase inhibitors (60%).

Patients were followed for an average of 16 months (range, 0-33 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 (CV) mortality [defined as sudden cardiac death or death due to progression of congestive heart failure (CHF), stroke, or other CV causes] or CV hospitalization (defined as hospitalization for progression of CHF, ventricular arrhythmias, acute myocardial infarction, or stroke). 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 allcause mortality are shown in Figure 1 and the components of mortality are provided in Table 1.

Table 1. Components of All-Cause Mortality in EPHESUS
	INSPRA ä(N=3319) n (%)	Placebo(N=3313) n (%)	Hazard Ratio	p-value
Death from any cause	478 (14.4)	554 (16.7)	0.85	0.008
CV Death	407 (12.3)	483 (14.6)	0.83	0.005
Non-CV Death	60 (1.8)	54 (1.6)
Unknown or unwitnessed death	11 (0.3)	17 (0.5)

Most CV deaths were attributed to sudden death, acute MI, and CHF.

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 CHF, 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 2.

Table 2. Rates of Death or Hospitalization in EPHESUS
Event		INSPRA ä n (%)	Placebo n (%)
CV death or hospitalization for progression of CHF, stroke, MI or ventricular arrhythmia1		885 (26.7)	993 (30.0)
	Death	407 (12.3)	483 (14.6)
	Hospitalization	606 (18.3)	649 (19.6)
CV death or hospitalization for progression of CHF, stroke, MI, ventricular arrhythmia, atrial arrhythmia, angina, CV procedures, or other CV causes (PVD; Hypotension)		1516 (45.7)	1610 (48.6)
	Death	407 (12.3)	483 (14.6)
	Hospitalization	1281 (38.6)	1307 (39.5)
All-cause death or hospitalization		1734 (52.2)	1833 (55.3)
	Death 1	478 (14.4)	554 (16.7)
	Hospitalization	1497 (45.1)	1530 (46.2)
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 CHF and patients greater than 75 years did not appear to benefit from the use of INSPRA. Such subgroup analyses must be interpreted cautiously.

Analyses conducted for a variety of CV biomarkers did not confirm a mechanism of action by which mortality was reduced.

Hypertension

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 ³65). 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 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.

Patients treated with INSPRA 50 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, angiotensin II receptor antagonists, calcium channel blockers, beta blockers, and hydrochlorothiazide. When administered concomitantly with one of these drugs INSPRA usually produced its expected antihypertensive effects.

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.

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