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Irbesartan

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in the Management of Hypertension

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Summary

Synopsis

Irbesartan inhibits the activity of angiotensin II (AII) via specific, selective non-competitive antagonism of the AII receptor subtype I (AT1) which mediates most of the known physiological activities of AII.

In patients with mild to moderate hypertension, once daily administration of irbesartan 150 or 300mg, with or without adjunctive antihypertensive agents, provides effective 24-hour BP control. Irbesartan reduced BP to a similar extent to enalapril and atenolol and to a significantly greater extent than losartan. The combination of irbesartan and hydrochlorothiazide resulted in additive antihypertensive effects. The drug is effective in the elderly and dosage adjustment is not required in these patients or in those with renal or hepatic failure.

Preliminary studies evaluating the efficacy of irbesartan in patients with heart failure have produced encouraging results.

Irbesartan is very well tolerated and neither the frequency nor the pattern of adverse events differed from those seen in placebo recipients, although headache was significantly more frequent with the latter. Similarly, the incidence of adverse events did not differ significantly between irbesartan and enalapril in patients who received either drug as monotherapy. Headache, upper-respiratory tract infection and musculoskeletal pain were the most common complaints.

Thus, irbesartan is an effective therapy for patients with mild to moderate hypertension and had an adverse event profile similar to that of placebo in clinical trials. On this basis it would appear to be an effective therapeutic option in this indication.

Pharmacodynamic Properties

Irbesartan selectively and noncompetitively binds to the angiotensin II (AII) receptor subtype 1 (AT1) inhibiting the activity of AII. Irbesartan has no affinity for the AII receptor subtype 2, or α1- and α2-adrenoceptor and serotonergic receptors. In volunteers single 150 and 300mg doses of the drug inhibited the pressor response to AII by ≈100% between 2 and 4 hours after administration. Single (5 to 400mg) or multiple doses (10 to 200 mg/day for 7 days) of irbesartan administered to volunteers did not significantly alter supine BP; however in salt-depleted individuals, single doses of irbesartan (50 or 100mg) decreased mean arterial pressure by 19 and 17mm Hg, respectively. Irbesartan effectively lowers BP in patients with hypertension (see Therapeutic Use summary) without affecting heart rate.

Treatment with irbesartan 5 to 900 mg/day induced substantial elevations in active renin, plasma renin activity and AII levels in healthy and salt-depleted volunteers and patients with hypertension or renal or hepatic dysfunction. Plasma renin levels remain high throughout the 24-hour dose interval and continue to increase with multiple-dose administration. Concomitant treatment with hydrochlorothiazide 25 mg/day resulted in greater increases (about 2-fold) in plasma renin activity and AII levels compared with irbesartan alone.

Irbesartan 10 or 50 mg/day (1 or 8 doses) did not affect renal blood flow or glomerular filtration rate in volunteers and, although a dose-related natriuretic effect occurred, neither bodyweight nor BP was significantly affected. In patients with hypertension, irbesartan 25 or 100 mg/day for 7 days did not alter 24-hour urinary sodium excretion. Uric acid excretion is unaffected by irbesartan.

In a study in patients with type 2 diabetes mellitus, proteinuria and mild to moderate hypertension (n = 47), mean baseline urinary protein levels decreased with irbesartan (8.5%) but increased with amlodipine (19.7%). Amlodipine was also associated with decreased creatinine clearance and increased serum creatinine levels relative to irbesartan.

A single dose of irbesartan 100 or 200mg reduced pulmonary capillary wedge pressure and systemic vascular resistance in 20 patients with heart failure [New York Heart Associadon (NYHA) Class II to IV]. Aortic wall and cardiac hypertrophy were reduced in spontaneously hypertensive rats treated with irbesartan.

Pharmacokinetic Properties

The bioavailability of irbesartan is 60 to 80% after oral administration and is not affected by food. After administration of irbesartan 50 to 300mg, maximum plasma drug concentrations (Cmax) are achieved within 1 to 2 hours (tmax). Values for Cmax and the area under the plasma concentration-time curve (AUG) are dose-related within this range, and are similar after single or multiple doses, indicating that drug accumulation does not occur. Irbesartan is about 90% bound to plasma proteins. Cytochrome P450 2C9 is the primary enzyme involved in the metabolism of irbesartan; no active metabolites have been identified.

After oral administration, about 20 and 30% of the drug is recovered in the urine and faeces, respectively. Oral and renal drug clearance rates are 18 and 0.07 L/h. About 1 % of single or repeated doses of irbesartan is excreted unchanged in the urine. In volunteers, the elimination half-life is about 12 to 20 hours and does not depend on dose.

The pharmacokinetic profile of irbesartan is not markedly influenced by gender. Cmax and AUC were significantly higher in older (aged ≥65 years) than in younger people, although these changes were not thought to be clinically significant. Similarly, compared with volunteers, no clinically significant changes in Cmax, tmax or AUC were apparent in patients with mild to moderate [creatinine clearance (CLcr) 1.8 to 4.3L/h] or severe (CLCR<1.8 L/h) renal failure, mild to moderate hepatic cirrhosis (Child-Pugh score 5 to 8) or in those undergoing haemodialysis.

Therapeutic Use

The andhypertensive effect of irbesartan 75 to 300 mg/day was evident within 2 weeks of initiation of therapy in patients with mild to moderate hypertension (DBP 95 to 110mm Hg) enrolled in double-blind trials. Irbesartan-induced reductions in BP were significant compared with placebo and, in general, were dose-related. Within 8 weeks up to 67% of irbesartan recipients had responded to drug therapy (defined as normalisation of BP or a ≥10mm Hg decrease in DBP) versus 20 to 30% of those treated with placebo; normal BP was achieved in up to 60% of patients who received irbesartan.

Similar mean reductions in trough sitting DBP and SBP were seen in patients with mild to moderate hypertension treated with irbesartan 75 to 300 mg/day, enalapril 10 to 40 mg/day and atenolol 50 or 100 mg/day. In these trials, the need for dosage titration to manage BP did not differ on the basis of treatment allocation and was required in 50 to 64% of patients. BP was normalised in 66% of irbesartan recipients versus 60% of enalapril recipients in 1 study and 61% of irbesartan versus 55% of atenolol recipients in the other.

Results from 1 study indicate that irbesartan 300 mg/day reduces BP to a significantly greater extent than losartan 100 mg/day in patients with mild to moderate hypertension.

In patients whose DBP remained ≥90mm Hg after 8 or 12 weeks’ treatment with irbesartan or atenolol alone, the addition of hydrochlorothiazide (with or without nifedipine) resulted in additional antihypertensive effects, and in 1 trial improved the overall response rate from 63 (atenolol monotherapy) or 72% (irbesartan monotherapy) to 88% (combination therapy).

Irbesartan 150 or 300 mg/day and enalapril 20 or 40 mg/day were similarly effective in patients with severe hypertension (DBP 115 to 130mm Hg); however, the majority of these patients (67 to 75%) required 2 or 3 additional antihypertensive agents for adequate control. After 10 weeks of treatment, 100% of patients treated with irbesartan (with or without hydrochlorothiazide, atenolol or nifedipine) had responded to therapy, with 59% achieving normal BP readings; results for enalapril recipients were similar (98 and 57%).

Few long term efficacy data for irbesartan are available. An interim analysis of an ongoing study reported an 85% response rate to irbesartan (with or without other antihypertensive drugs) in evaluable patients (≈40%) after ≥12 months therapy. The effects of irbesartan did not appear to differ on the basis of age (<65 and ≥65 years) or gender.

In patients with heart failure, irbesartan was more effective than placebo when added to existing therapy in one preliminary study, and as effective as lisinopril in another.

Tolerability

Pooled tolerability data from placebo comparisons involving 2606 patients show that irbesartan is well tolerated and, apart from the incidence of headache, neither the frequency nor the pattern of adverse events differs from placebo. Headache occurred significantly more frequently in placebo than in irbesartan recipients. The most frequently reported adverse events were headache, upper respiratory tract infection, musculoskeletal pain, dizziness and fatigue. 3.3% of irbesartan recipients versus 4.5% of placebo recipients discontinued therapy because of adverse events.

In 1 study, cough occurred more frequently in patients treated with enalapril than irbesartan (17 vs 10%) but the difference was not statistically significant.

Dosage and Administration

Irbesartan is administered orally and, in doses between 150 and 300 mg/day, reduces BP in patients with mild to moderate hypertension. In most patients, therapy should be initiated with irbesartan 150 mg/day and titrated upward to a maximum of 300 mg/day based on BP response and tolerability. The addition of hydrochlorothiazide 6.25 to 25 mg/day to irbesartan induces a further antihypertensive response. No dosage adjustment is needed in older patients (≥65 years) or those with renal or hepatic dysfunction.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Jane C. Gillis & Anthony Markham

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  1. Jane C. Gillis
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Correspondence to Anthony Markham.

Additional information

Various sections of the manuscript reviewed by: V.V.S. Bonarjee, Cardiology Division, Central Hospital in Rogaland, Stavanger, Norway; M. Burnier, Division of Hypertension, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; G. Carruthers, Department of Medicine, University of Western Ontario, University Hospital, London, Ontario, Canada; J. Chalmers, Department of Medicine, Flinders Medical Centre, Bedford Park, South Australia, Australia; B. Dahlöf, Clinical Experimental Research Laboratory, Östra University Hospital, Göteborg University, Gothenburg, Sweden; N.M. Kaplan, Hypertension Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA; M. McIntyre, University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; C. Ponticelli, Divisione di Nefrologia e Dialisi, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Maggiore di Milano, Milan, Italy; C. Rosendorff, Department of Medicine, Mount Sinai School of Medicine, New York, New York, USA; A.I. van den Meiracker, Department of Internal Medicine, University Hospital Dijkzigt, Rotterdam, The Netherlands.

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Gillis, J.C., Markham, A. Irbesartan. Drugs 54, 885–902 (1997). https://doi.org/10.2165/00003495-199754060-00007

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