IRBESARTAN, Avapro®, Bristol-Myers Squibb

Hypertension is the most prevalent cardiovascular disease in the US, affecting as many as one quarter of the adult population. Furthermore, hypertension is an independent risk factor for cardiovascular disease and is associated with an increased incidence of stroke and coronary heart disease. Although there have been many advances in the treatment over the past several decades, less than 25% of all hypertensive patients have their blood pressure adequately controlled with available therapies.

The renin-angiotensin-aldosterone system (RAAS) plays an essential role in the regulation of blood pressure. Renin, a proteinase enzyme, is secreted by the kidney in response to a reduction in renal blood flow, blood pressure or sodium concentration. Renin then converts angiotensinogen, which is secreted by the liver, to the decapeptide angiotensin I (AI). AI is cleaved by angiotensin converting enzyme (ACE) to the octapeptide angiotensin II (AII). AII produces potent vasoconstriction via interaction with vascular angiotensin receptors (AT receptors). AII also promotes aldosterone secretion and therefore sodium retention by stimulation of angiotensin receptors present on the adrenal cortex. These actions result in elevated blood pressure secondary to the vasoconstriction and enhanced cardiac output secondary to sodium retention. In addition to its normal regulatory role, the RAAS also contributes to pathological conditions such as renovascular hypertension, essential hypertension and congestive heart failure. Thus over the past several decades research efforts have been directed toward developing drugs capable of suppressing of RAAS by 1). inhibiting renin release, 2). blocking the formation of AII via inhibition of ACE, or 3). antagonism of AII at its physiologic receptors. In the past most clinically relevant success involved the development of ACE inhibitors (ACEIs), beginning with the introduction of captopril in 1981, followed by enalapril (Vasotec®), lisinopril (Prinivil®, Zestril®), benazepril (Lotensin®), fosinopril (Monopril®), quinapril (Accupril®), ramipril (Altace®), moexipril (Univasc®) and trandolapril (Mavik®). ACEIs have been successfully employed in the management of various forms of hypertension as well as congestive heart failure. However, ACE has other physiologic actions not related to the regulation of RAAS, including the degradation of bradykinin and other peptides including substance P. These additional actions are also inhibited by ACEIs, and this may account for some of the adverse reactions of these drugs including dry cough. Thus in recent years renin inhibitors and AII receptor antagonists were targeted for development as more specific inhibitors of the RAAS and as a direct approach to block the system independent of AII production. These efforts led to the introduction in recent years of several non-peptide heterocyclic AII antagonists including losartan (Cozaar®), followed by valsartan (Diovan®) and now irbesartan. Irbesartan is well-absorbed orally, long-acting allowing for once-daily administration, and unlike losartan, does not exert a uricosuric effect. Irbesartan also is reported to demonstrate dose-response efficacy while maintaining placebo-level side effects at doses.

Pharmacology^1-4:

Angiotensin II (AII) is the primary vasoactive hormone of the renin-angiotensin system and an important contributor toward the pathophysiology of hypertension. AII is formed from angiotensin I (AI) by the action of the enzyme ACE. Once formed AII interacts with AT1 receptors present on vascular smooth muscle to produce vasoconstriction, and adrenal AT1 receptors to promote the secretion of aldosterone and both of these actions contribute toward elevated blood pressure. Irbesartan, like valsartan and losartan, functions as specific and competitive AT1 receptor antagonist, thereby blocking the actions of the endogenous ligand AII. Like losartan and valsartan, irbesartan is a considerably weaker antagonist at AT2 receptors, a receptor found in many tissues but apparently not associated with cardiovascular homeostasis. None the angiotensin antagonists inhibit ACE, nor do they bind to or block other hormone or neurotransmitter receptors or ion channels known to be important in cardiovascular regulation. Therefore, unlike ACE inhibitors, irbesartan does not result in accumulation of bradykinin, a substance implicated in the dry cough frequently assocaited with ACEIs. Furthermore studies in healthy volunteers suggest that angiotensin antagonists have no effects on renal function, prostaglandin levels, fasting triglycerides, total or HDL cholesterol or fasting glucose levels. While there does appear to be a small uricosuric effect associated with losartan, irbesartan does not appear to alter serum uric acid levels. Irbesartan produces a dose- dependent rise in plasma renin activity and plasma AII levels in hypertensive patients as a result of removal of the negative feedback of AII. However, the resulting increased plasma renin activity and angiotensin II circulating levels are insufficient to alter the effects of these drugs on blood pressure. In healthy subjects irbesartan (150 or 300 mg), like other angiotensin antagonists, inhibits the pressor effects of infused AII producing peak inhibition of both systolic and diastolic blood pressure rise within 2-4 hours with residual effects persisting for 24 hours..

In a number of multicenter, randomized, placebo-controlled, double-blind studies in patients with mild to moderate hypertension, statistically significant reductions in trough systolic and diastolic blood pressures were observed in patients receiving irbesartan in doses of 75 mg daily or greater. Greater reductions in blood pressure occurred when the dose was increased, but this effect leveled off at about 300 mg. The blood pressure lowering effects of irbesartan were apparent after the first dose, and reached maximal effect within 4-6 weeks. Irbesartan was found to be effective in reducing blood pressure regardless of patient age, gender or race. However, the effect in black patients, typically a low renin population, is somewhat lower. In comparative trials irbesartan was shown to be at least as effective as hydrochlorothiazide, atenolol and the full dosage of enalapril. And in combination trials, greater reductions in blood pressure were observed when irbesartan was combined with the diuretic hydrochlorothiazide. As a result of these findings, irbesartan is indicated for the once daily treatment of hypertension and may be used alone or in combination with other antihypertensive agents.

The safety of irbesartan has been evaluated in clinical trials involving more than 5000 subjects. More than 1000 of these patients were treated with the drug for over 6 months, and approximately 400 patients have used the drug for a year or more. Overall irbesartan was well tolerated with the incidence of adverse reactions similar to placebo. The withdrawal rate due to adverse events was 3.3% in the irbesartan-treated group versus 4.5% among placebo-treated patients. Adverse events typically were mild and transient and not related to dose of the drug. The most common adverse reactions contributing to discontinuation were headache (0.6%) and dizziness (0.3%); yet headache occurred more often in the placebo-treated group (1.1%). Adverse events reported in at least 1% of the irbesartan patients and at a higher percentage than placebo included diarrhea (3%), dyspepsia or heartburn (2%), musculoskeletal trauma (2%) and upper respiratory tract infection (9%). Cough was reported with equal frequency in both the irbesartan and placebo treated patients (ca 3%). There were no reports of angioedema, an adverse event seen occasionally with ACEIs. The frequency of reports of fatigue (4.3%), peripheral edema (1.5%) and sexual dysfunction (0.7%) were similar in both the irbesartan and placebo treated groups. The incidence of hypotension and orthostatic hypotension was low in the irbesartan group (not significantly different from placebo) and unrelated to dose. Also, reflex tachycardia was not seen in doses up to100 mg in normotensive, salt-depleted males. Alterations in laboratory test data attributed to irbesartan occurred infrequently.

No significant pharmacokinetic or pharmacodynamic drug interactions have been uncovered in studies in which irbesartan was used concurrently with hydrochlorothiazide, nifedipine, warfarin, digoxin, tolbutamide or antacids. In vitro studies showed significant inhibition of the oxidative metabolism of irbesartan with cytochrome P450 2C9 substrates or inhibitors (sulphenazole, tolbutamide, nifedipine), but no clinically significant adverse consequences have been observed from this interaction. Additionally, in vitro data suggest there are no interactions with drugs whose metabolism is dependent on cytochrome P450 isozymes 1A1, 1A2, 2A6, 3A4, 2B6, 2D6 or 2E1 and thus no significant interactions would be anticipated.

The pharmacokinetics of irbesartan is compared to the other available angiotensin receptor antagonists in the Table. Irbesartan is more completely absorbed from GI tract than other AT antagonists and reaches peak plasma concentrations within 2 hours. Irbesartan is not as extensively bound to plasma proteins and does not require metabolism to the active form. It is metaboilized hepatically to inactive metabolites via cytochrome P450 2C9 (CYP29). It is excreted by both biliary and renal routes and has a longer elimination half-life (11-15 hrs) than other angiotensin antagonists. The pharmacokinetics of irbesartan are not significantly altered by renal or mild-to-moderate hepatic impairment, age or by co- administration of hydrochlorothiazide.

Dosage and Administration^4-8:

Irbesartan is available as white and off-white biconvex oval tablets in 75, 150 and 300 mg strengths. The drug may be administered with or without food and the recommended initial dose of irbesartan is 150 mg once daily. Patients treated vigorously with diuretics or on hemodialysis (volume-depleted patients), however, should receive an initial dose of 75 mg. Those patients requiring further blood pressure reduction may be titrated to 300 mg once daily. It is unlikely that higher doses or twice daily dosing will produce additional antihypertensive effects. No dosage adjustment is necessary in elderly patients, or those with hepatic impairment or mild to severe renal impairment. If blood pressure is not controlled by irbesartan alone, another antihypertensive may be added. Also, low doses of a diuretic such as hydrochlorothiazide may be added to improve therapeutic effect. Irbesartan therapy should be avoided during pregnancy.

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5. Guthrie RM, Saini R, Hannah S, et al. Dose-related reductions in blood pressure with irbesartan, the angiotensin II receptor antagonist. Am. J. Hyperten. 1997, 10 (part 2):172A.

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8. Stumpe KO, Haworth D, Hoglund C, et al. Comparison of angiotensin II receptor antagonist irbesartan and atenolol for the treatment of hypertension. J. Hypertens. 1997, 15 (suppl 4):S115.

9. Marino MR, Langenbacher KM, Raymond RH, et al. Pharmacokinetics (PK) and antihypertensive effects of irebesartan (an AII receptor antagonist) in subjects with hypertension. J. Hypertens. 19967, 14 (suppl 1):S348.

10. Marino MR, Langenbacher KM, Ford NF, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of irbesartan after single and multiple doses in healthy male subjects. Clin. Pharmacol. Ther. 1997, 61:207.

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