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Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan is a specific insurmountable antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium homeostasis. Irbesartan does not require metabolic activation for its activity.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of the angiotensin II (AT1 subtype) receptors localized on vascular smooth muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (a receptor that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (ie, renin, angiotensin converting enzyme [ACE]) or affect other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan blockade of AT1 receptors interrupts the feedback loop within the renin-angiotensin system, resulting in increases in plasma renin levels and angiotensin II levels. Aldosterone plasma concentrations decline following irbesartan administration, however, serum potassium levels are not significantly affected (mean increase of <0.1 mEq/L) at the recommended doses. Irbesartan has no notable effects on serum triglycerides, cholesterol or glucose concentrations. There is no effect on serum uric acid or urinary uric acid excretion.
Clinical Efficacy/Clinical Studies: The blood pressure-lowering effect of irbesartan is apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 4-6 weeks. In long-term follow-up studies, the effect of irbesartan was maintained for over one year.
Once-daily doses of up to 900 mg provided dose-related decreases in blood pressure. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (ie, 24 hours after dosing) by an average of 8-13/5-8 mmHg (systolic/diastolic) greater than those associated with placebo. The trough effects are 60-70% of the corresponding peak diastolic and peak systolic responses. Optimal effects on 24-hour blood pressure are achieved with once daily dosing.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects are infrequent, but as with ACE inhibitors, may be expected to occur in patients who are sodium-depleted and/or volume-depleted.
The blood pressure-lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mmHg (systolic/diastolic).
The effectiveness of irbesartan is not influenced by age or gender. As is the case with other drugs that affect the renin-angiotensin system, black patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with low-dose hydrochlorothiazide (eg, 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.
After withdrawal of irbesartan, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed.
Hypertension and type 2 diabetic renal disease: The Irbesartan Diabetic Nephropathy Trial (IDNT) was a multicenter, randomized, controlled, double-blind, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1715 hypertensive patients with type 2 diabetes (proteinuria ≥900 mg/day and serum creatinine 1.0 - 3.0 mg/dL) the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. In addition, a secondary endpoint, the effect of Aprovel on the risk of fatal or non-fatal cardiovascular events was assessed. Patients were randomized to receive Irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were then titrated to a maintenance dose of 300 mg Irbesartan, 10 mg amlodipine, or placebo as tolerated. Aprovel demonstrated a 20% relative risk reduction in the composite primary endpoint (first occurrence of any of the following: doubling of serum creatinine, end-stage renal disease or all-cause mortality) compared to placebo (p=0.024) and a 23% relative risk reduction compared to amlodipine (p=0.006). Similar blood pressure was achieved in the Aprovel and amlodipine groups. There was no significant difference in the assessment of fatal or non-fatal cardiovascular events (cardiovascular death, non-fatal myocardial infarction, hospitalization for heart failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation) among the three treatment groups.
The effects of irbesartan on renal events were not uniform across all subgroups: they appeared less favorable in women and non-whites. Subgroup analyses are difficult to interpret and it is not known whether these observations represent true differences or chance effects.
The study of the Effects of Irbesartan on MicroAlbuminuria in Hypertensive Patients with Type 2 Diabetes Mellitus (IRMA 2) was a multicenter, randomized, placebo-controlled, double-blind morbidity study conducted in 590 hypertensive patients with type 2 diabetes, microalbuminuria (20-200 mcg/min; 30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dL in males and ≤ 1.1 mg/dL in females). The study examined as a primary endpoint the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate [AER] > 200 mcg/min [> 300mg/day] and an increase in AER of at least 30% from baseline). In addition, after one and two years of treatment, the effect of Aprovel on the change in overnight AER and the change in 24-hour creatinine clearance was assessed. Aprovel 300 mg demonstrated a 70% relative risk reduction in the development of clinical (overt) proteinuria compared to placebo (p=0.0004). Aprovel 150 mg demonstrated a 39% relative risk reduction in the development of proteinuria compared to placebo (p=0.085). The slowing of progression to clinical (overt) proteinuria was evident as early as three months and continued over the 2-year period. The decline in 24-hour creatinine clearance did not differ significantly among the 3 groups. Regression to normoalbuminuria (<20 mcg/min; <30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%).
Pharmacokinetics: Absorption: Irbesartan is an orally active agent and does not require biotransformation for its activity. Peak plasma concentration occurs at 1.5-2 hours after oral administration. Following oral administration, irbesartan is rapidly and completely absorbed. The absolute oral bioavailability of irbesartan is 60-80%. Food does not affect the bioavailability.
Distribution: Irbesartan is approximately 96% protein-bound in plasma and has negligible binding to cellular components of blood.
The volume of distribution is 53-93 Liters.
Metabolism: In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following oral or intravenous administration of 14C irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan does not induce nor inhibit isoenzyme CYP3A4. Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolized by, nor does it substantially induce or inhibit, most isoenzymes commonly associated with drug metabolism (ie, CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1).
Elimination: Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered radioactivity after an oral or intravenous dose of 14C irbesartan is recovered in urine with the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan. The terminal elimination half-life (t½) of irbesartan is 11-15 hours. The total body clearance of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5 mL/min is renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily dosing.
Special Populations: Gender: In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan were observed in females than in males, although, following multiple dosing, males and females did not show differences in either accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.
Elderly patients: In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and hepatic function, the plasma AUC and peak plasma concentrations (Cmax) of irbesartan are approximately 20%-50% greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is comparable. No significant age-related differences in clinical effect have been observed.
Hepatic impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.
Renal impairment: In patients with renal impairment (regardless of degree) and in hemodialysis patients, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis.
Race: In black and white normotensive subjects, the plasma AUC and t½ of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (Cmax) of irbesartan are essentially equivalent.
