Sign Out
Irbesartan: Mechanism of action: Irbesartan is a specific angiotensin II receptor antagonist (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system involved in the pathophysiology of hypertension and sodium homeostasis. Irbesartan does not require metabolic activation to exert its effect.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of angiotensin II receptors (AT1 subtype) located on vascular smooth muscle cells and the adrenal cortex. Irbesartan has no agonist activity at the AT1 receptor and has a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (receptor that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit enzymes involved in the renin-angiotensin system (i.e., angiotensin converting enzyme [ACE]) or have an effect on other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan AT1 receptor blockade disrupts the renin-angiotensin feedback loop, increasing plasma renin and angiotensin II levels. Following irbesartan administration, aldosterone plasma concentrations decrease; however, no significant effect on serum potassium levels can be observed at the recommended doses (mean increase <0.1 mEq/L). Irbesartan has no notable effect on serum triglycerides, cholesterol or glucose concentrations; it has no effect on serum uric acid levels or on urinary uric acid excretion.
Pharmacodynamic properties: The blood pressure lowering effect of irbesartan is apparent after the first dose and becomes substantial within 1-2 weeks, with maximal effect at 4-6 weeks. In long-term follow-up studies, the effect of irbesartan was maintained for more than one year.
A single dose of up to 900 mg per day produced a dose-dependent decrease in blood pressure. Once daily doses of 150-300 mg decrease trough supine or seated blood pressures (i.e., 24 hours after dosing) by an average of 8-13/5-8 mmHg (systolic/diastolic), which is higher than that observed with placebo. The effects measured at trough are 60-70% of the corresponding peak diastolic and systolic effects. 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 sodium- and/or volume-depleted patients.
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 higher blood pressure reduction at trough of 7-10/3-6 mm Hg (systolic/diastolic) compared to placebo.
Neither age or gender has an effect on irbesartan efficacy. As is the case with other drugs that have an effect on the renin-angiotensin system, black patients have a notably lower response to irbesartan monotherapy. When irbesartan is administered concomitantly with low-dose hydrochlorothiazide (e.g., 12.5 mg daily), the antihypertensive response in black patients is similar to that in white patients.
After withdrawal of irbesartan, blood pressure gradually returns to baseline. Rebound hypertension has not been observed.
Amlodipine: Mechanism of action: Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina symptoms has not been determined but amlodipine reduces total ischemic burden in the following two ways: 1) Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements; 2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
Pharmacodynamic properties: In patients with hypertension, once daily dosing produces significant reductions of blood pressure in both the supine and standing positions over a period of 24 hours. Due to the slow onset of action, acute hypotension is not associated with amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression. In addition, it decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Irbesartan/Amlodipine Combination: Concomitant administration of irbesartan and amlodipine, whether in a fixed dose combination tablet or the free combination, has no effect on the bioavailability of the individual components.
The three fixed dose combinations of irbesartan and amlodipine (150 mg/10 mg, 300 mg/5 mg, and 300 mg/10 mg) are bioequivalent to the free dose combinations (150 mg/10 mg, 300 mg/5 mg, and 300 mg/10 mg) both in terms of rate and extent of absorption.
When given separately or concomitantly at 300 mg and 10 mg dose levels, time to mean peak plasma concentrations of irbesartan and amlodipine remain unchanged, i.e. 0.75-1 hour and 5 hours after administration, respectively. Similarly, Cmax and AUCs are in the same range resulting in a relative bioavailability of 95% for irbesartan and 98% for amlodipine whether the two drugs are administered concomitantly.
The mean half-life values for irbesartan and amlodipine, administered alone or in combination, are similar: 17.6 hours versus 17.7 hours for irbesartan, and 58.5 hours versus 52.1 hours for amlodipine. Elimination of irbesartan and amlodipine is unchanged whether the drugs are administered alone or concomitantly.
The pharmacokinetic profile of both drugs appears to be linear over the co-administered dose range (i.e. between 150 mg and 300 mg for irbesartan, and between 5 mg and 10 mg for amlodipine).
Pediatric patients: No information is available for the fixed dose combination.
CLINICAL EFFICACY/CLINICAL STUDIES: The clinical evidence for the efficacy of the fixed-dose combination of irbesartan and amlodipine is derived from two studies: the I-ADD and I-COMBINE studies. Both studies were multi-center, prospective, randomized, open-label, parallel-group studies with blinded endpoint evaluation design. The studies were conducted in patients with established essential hypertension, having uncontrolled blood pressure (mean systolic blood pressure [SBP] ≥145 mmHg) after at least four weeks of treatment with irbesartan 150 mg (I-ADD) or amlodipine 5 mg (I-COMBINE).
Both studies consisted of three treatment periods, A, B, and C. During Period A, all patients received amlodipine 5 mg or irbesartan 150 mg, once daily, for seven to ten days. At the end of Period A, if a patient's mean SBP was <135 mmHg, he or she was withdrawn from the respective study.
In I-ADD, patients (n=325) were randomized following Period A to receive either irbesartan 150 mg or fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily for five weeks (Period B).
At Week 5, the doses were increased (forced titration) to irbesartan 300 mg or the fixed-dose combination irbesartan/amlodipine 300 mg/5 mg once daily and continued for five weeks.
In I-COMBINE, patients (n=290) were randomized following Period A to receive either amlodipine 5 mg or the fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily for five weeks (Period B). At Week 5, the doses were increased (forced titration) to amlodipine 10 mg or fixed-dose combination irbesartan/amlodipine 150 mg/10 mg once daily and continued for five weeks (Period C).
In I-ADD, the primary endpoint was the change in SBP measured at home at Week 10.
In I-COMBINE, the primary endpoint was the change in SBP measured at home at Week 5. Secondary endpoints were home diastolic blood pressure (DBP) and office blood pressure measurement (OBPM) as well as the percentage of controlled patients (mean home SBP <135 mmHg) and responder patients (mean home SBP <135 mmHg and mean home DBP <85 mmHg) at Week 10 for both studies.
Results of both studies demonstrated significantly greater efficacy of the fixed-dose combination compared to amlodipine alone or irbesartan alone (see Tables 1 and 2).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imagePharmacokinetics: Irbesartan: Irbesartan is an orally active agent that does not require biotransformation to exert its effect. Following oral administration, irbesartan is rapidly and completely absorbed. Peak plasma concentrations are reached 1.5-2 hours after oral administration. The absolute oral bioavailability of irbesartan is 60-80%. Food has no effect on irbesartan bioavailability.
Irbesartan is approximately 96% plasma protein bound, and has negligible binding to cellular components of blood. The volume of distribution is 53-93 L/Kg.
In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following oral or intravenous administration of 14C-labeled irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The main circulating metabolite is irbesartan glucuronide (approximately 6%). Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; the isoenzyme CYP3A4 has a negligible effect. Irbesartan is not metabolized by most isoenzymes commonly involved in drug metabolism (i.e., CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1), and it does not significantly induce or inhibit these enzymes. Irbesartan does not induce or inhibit the isoenzyme CYP3A4.
Irbesartan and its metabolites are eliminated by both the biliary and renal routes. About 20% of the administered radioactivity after administration of either an oral or intravenous dose of 14C-labeled irbesartan is recovered in urine, with the remainder recovered in the feces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
The terminal elimination half-life (t1/2) 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 reached within three days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma after repeated once-daily dosing.
In hypertensive subjects, higher irbesartan plasma concentrations were observed in females compared to males (11-44%). Following multiple dosing, however, no differences in either accumulation or elimination half-life were observed between males and females. No gender-specific differences in clinical effect have been observed.
In elderly normotensive subjects (males and females, 65-80 years) with clinically normal renal and hepatic function, irbesartan plasma AUC and peak plasma concentrations (Cmax) were approximately 20-50% higher than in younger subjects (18-40 years). Regardless of age, elimination half-life is comparable.
No significant age-related differences in clinical effect have been observed.
In black and white normotensive subjects, irbesartan plasma AUC and t1/2 are approximately 20-25% higher in black subjects compared to white subjects, whereas irbesartan peak plasma concentrations (Cmax) were essentially equivalent.
In patients with renal impairment (regardless of degree) and in hemodialysis patients, the pharmacokinetic profile of irbesartan is not significantly altered. Irbesartan is not removed by hemodialysis.
In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetic profile of irbesartan is not significantly altered.
Amlodipine: After oral administration of therapeutic doses, amlodipine is well absorbed, with peak blood levels reached between 6 and 12 hours post administration. Absolute bioavailability is estimated to be between 64 and 90%. The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma protein. Food intake does not have an effect on amlodipine absorption.
The terminal plasma elimination half-life is about 35-50 hours and is compatible with once daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Use in elderly patients: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to decrease, resulting in increases in AUC and elimination half-life in elderly patients.
Increases in AUC and elimination half-life in patients with congestive heart failure were as expected in this age group.
Pediatric patients: A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine doses of between 1.25 and 20 mg given either once or twice daily.
In children 6 to 12 and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/h, respectively, in males and 16.4 and 21.3 L/h, respectively, in females. Large variability in exposure between individuals was observed. Data reported in children younger than 6 years are limited.
Patients with hepatic insufficiency: see Precautions.
