Erschienen in:
01.05.2000 | Adis Drug Evaluation
Irbesartan
An Updated Review of its Use in Cardiovascular Disorders
verfasst von:
Anthony Markham, Caroline M. Spencer, Blair Jarvis
Erschienen in:
Drugs
|
Ausgabe 5/2000
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Summary
Abstract
Irbesartan interrupts the renin-angiotensin system via selective blockade of the angiotensin II subtype 1 receptor; the latter being responsible for the pressor related effects of angiotensin II.
As treatment for mild to moderate hypertension, irbesartan 150 mg/day controlled diastolic BP in 56% of patients according to pooled data from several phase III studies and 77% of patients in a large phase IV study. In comparative trials, irbesartan was significantly more effective than losartan and valsartan as treatment for mild to moderate essential hypertension and as effective as enalapril or atenolol. Results from many studies show an additive antihypertensive effect when hydrochlorothiazide is added to irbesartan monotherapy. The drug also induces statistically significant regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy, and preliminary evidence suggests it has beneficial haemodynamic effects in patients with heart failure.
Irbesartan is very well tolerated, exhibiting an adverse event profile similar to that seen with placebo in comparative trials.
In conclusion, although the role of irbesartan as a treatment for heart failure is little clearer than it was 2 years ago, the place of the drug in the management of hypertension is now better established. There is evidence to suggest the drug may have a role as initial therapy for hypertension, although formal recommendation in management guidelines will almost certainly not occur until long term morbidity and mortality benefits are established.
Pharmacodynamic Properties
Irbesartan is a selective angiotensin II subtype 1 (AT1) receptor antagonist, having no agonist activity and no affinity for the AT2 receptor. The drug has no affinity for α1- or α2-adrenoceptors or serotonergic receptors.
In the rabbit aorta model, increasing concentrations of irbesartan caused a parallel rightward shift of the angiotensin II concentration contractile response curve and a progressive reduction in maximal response. On this basis the receptor effects of irbesartan have been described as insurmountable.
In healthy volunteers, oral irbesartan (150mg), valsartan (80mg) or losartan (50mg) induced peak inhibition of the angiotensin II-induced pressor response after ∼4 hours; however, the effects of irbesartan were significantly greater, and lasted longer, than those of valsartan which were significantly greater than those of losartan.
Irbesartan has been shown to inhibit angiotensin II-induced proliferation of cultured human aorta smooth muscle cells in vitro and had anti-atherosclerotic effects in genetically hypercholesterolaemic rabbits in vivo. In animals subjected to experimental heart failure, myocardial infarction or aortic stenosis, administration of irbesartan decreased the development of ventricular hypertrophy. In patients with heart failure, single doses of irbesartan produced dose-dependent acute improvement in pulmonary capillary wedge pressure. Similar effects were seen in a further study that assessed both the acute and medium term (12-week) effects of the drug.
Several studies have shown that irbesartan improves glomerulosclerosis and reduces proteinuria in rats with experimentally induced renal failure.
In healthy volunteers, a 50mg dose of irbesartan increased renal vasodilation zbut did not affect arterial BP or glomerular filtration rate (GFR). The drug increased sodium excretion but did not exhibit a uricosuric effect. Irbesartan prevented arterial hypertension and renal vasoconstriction in response to exogenous angiotensin II infusion in this study. Similar effects were observed in a 6-week comparison with enalapril in patients with hypertension. Both drugs caused renal vasodilation without significantly affecting GFR; however, the effects of irbesartan occurred later in the dosage interval and were more prolonged than those of enalapril.
Pharmacokinetic Properties
Irbesartan has a bioavailability of ∼60 to 80% and this is not affected by concomitant food intake. In healthy volunteers, peak plasma irbesartan concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increase linearly with increasing dosage although the time to peak plasma concentration (tmax) is dose-independent. The drug is 96% bound to plasma proteins and has a steady-state volume of distribution of 53 to 93L.
In patients with hypertension treated with irbesartan 300 mg once daily, steady-state irbesartan Cmax (3.9 mg/L) tmax (1.5 hours) and AUCτ (22.0 mg/L · h) values were very similar to those observed in healthy volunteers.
Single or multiple oral doses of irbesartan 300 mg/day produced apparent total and renal clearance values of ∼18 and 0.07 L/h. Elimination half-lives of 11 to 15 hours, independent of dosage, have been reported.
In healthy volunteers, 20 and ∼30% of radioactivity from a single 150mg dose of [14C] irbesartan was recovered from urine and faeces, respectively. After oral or intravenous administration of 14C-labelled irbesartan >80% of plasma radioactivity was attributable to unmetabolised irbesartan. The primary metabolic fate of the drug appears to be oxidation via cytochrome P450 (CYP) isoform 2C9.
Multiple oral doses of irbesartan ≤300 mg/day had no clinically relevant influence on the pharmacokinetic profiles of warfarin or nifedipine but a 150mg dose increased the AUCτ of fluconazole.
Therapeutic Use
Pooled data from 8 studies show that monotherapy with irbesartan ≥150 mg/day for 6 to 12 weeks induces a clinically significant reduction in BP. 56% of patientsresponded to an irbesartan dosage of 150 mg/day (response was defined as an endpoint DBP <90mm Hg or a reduction of ≥10mm Hg from baseline); antihy-pertensive effects increased with increasing dosage, reaching a plateau at ≥300 mg/day. Ambulatory monitoring has shown that irbesartan 150mg once daily controls 24-hour BP as effectively as 75mg twice daily. A phase IV study involving 7314 evaluable patients reported a 77% response rate to irbesartan 150 mg/day as monotherapy.
In randomised double-blind studies, irbesartan was significantly more effective than losartan or valsartan in patients with mild to moderate essential hypertension. Irbesartan was as effective as enalapril or atenolol in other well-designed studies.
Pooled results from 1- to 2-year extensions of studies evaluating the efficacy of irbesartan ≤300 mg/day ± hydrochlorothiazide initially in a total of 1006 patients with hypertension revealed a clinically relevant reduction from baseline in BP after 2 to 4 months treatment that plateaued after 6 to 8 months. BP normalised in 83% of patients and the overall response rate was 90% in this analysis.
A matrix study evaluating several combinations of irbesartan and hydrochlorothiazide showed that regimens containing higher dosages of irbesartan appeared to have greater antihypertensive efficacy than those containing higher dosages of hydrochlorothiazide.
In a further study, addition of hydrochlorothiazide to irbesartan monotherapy in patients not responsive to the latter resulted in additive antihypertensive effects within 2 weeks.
In the reverse situation, addition of irbesartan to hydrochlorothiazide was found to be significantly more effective than hydrochlorothiazide plus placebo.
Results from several preliminary studies show that irbesartan induces statistically significant regression of left ventricular mass (LVM) in patients with hypertension. Two randomised double-blind studies have compared the effects of irbesartan and atenolol on left ventricular hypertrophy in patients with hypertension. In both studies LVM-index decreased to a greater extent with irbesartan than with atenolol.
The antihypertensive efficacy of irbesartan ≤300 mg/day was not influenced by mild to severe renal impairment in a noncomparative study in patients with hypertension and renal impairment; however, the effects of the drug were enhanced in patients undergoing haemodialysis compared with those with mild to severe renal impairment.
A 12-week randomised double-blind study evaluating the effects of irbesartan 12.5 to 150 mg/day in patients with heart failure reported that significantly fewer patients receiving higher dosages (≥75 mg/day) of irbesartan discontinued treatment or were hospitalised because of worsening heart failure.
Tolerability
Analysis of pooled tolerability data from 9 studies (mean treatment duration 9 weeks) involving 2606 patients with mild to moderate hypertension revealed no clinically relevant difference between irbesartan and placebo in the incidence of any adverse event. The most common adverse event in these trials, headache, occurred significantly more frequently in placebo (17%) than in irbesartan-treated patients (12%). All other adverse events occurring at a rate ≥2% had a similar incidence in each group. 21% of irbesartan versus 20% of placebo recipients experienced ≥1 adverse event.
In a post-marketing surveillance study 1232 of 9009 patients (13.7%) reported a total of 1766 events of which 1257 were considered related to irbesartan. Most adverse events were mild to moderate in severity; the incidence of headache and dizziness, the most common adverse events, were 1.8 and 1.9%, respectively. 119 adverse events considered serious occurred in 85 patients; of these 20 were thought to be treatment related.
Dosage and Administration
Irbesartan is indicated for the treatment of hypertension in adults, either alone or in combination with other antihypertensive agents. The recommended starting dosage of irbesartan is 150mg administered once daily. In patients who are volume or salt depleted as a result of vigorous treatment with diuretics or haemodialysis, a lower starting dosage (75 mg/day) is recommended. The maximum recommended dosage of irbesartan is 300mg once daily. In patients who do not achieve an adequate BP response to monotherapy, the combination of irbesartan plus hydrochlorothiazide 12.5 mg/day may be used. Dosage adjustments are not required in elderly patients or in patients with renal or hepatic impairment.