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Candesartan Cilexetil

A Review of its Use in Essential Hypertension

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Summary

Abstract

Candesartan cilexetil is completely converted to the nonpeptide angiotensin II receptor blocker candesartan during absorption from the gastrointestinal tract. Candesartan selectively blocks and dissociates slowly from the angiotensin II subtype 1 (AT1) receptor which mediates most of the known activities of angiotensin II.

When administered once daily, oral candesartan cilexetil 8 to 32mg dose-dependently and effectively reduces blood pressure in patients with mild to moderate essential hypertension. In comparative studies, candesartan cilexetil 8 mg/day was as effective as usual therapeutic dosages of enalapril, losartan potassium, hydrochlorothiazide and amlodipine. One study showed candesartan cilexetil 16 mg/day to be more effective than losartan potassium 50 mg/day. Furthermore, the combination of candesartan cilexetil with either hydrochlorothiazide or amlodipine resulted in additive antihypertensive effects.

Preliminary evidence suggests that the blood pressure-lowering effects of candesartan cilexetil are associated with the prevention or improvement of end-organ damage in patients with hypertension. However, this requires further confirmation in clinical studies. Candesartan cilexetil improves insulin sensitivity in patients with hypertension and does not affect glucose homeostasis or the serum lipid profile in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus.

Candesartan cilexetil is well tolerated in patients with hypertension. Pooled data indicate that the tolerability profile of the drug is not significantly different from that of placebo, with headache being the most commonly reported event. Adverse events are not dose related and are mostly mild to moderate in severity. Candesartan cilexetil is better tolerated than enalapril, primarily because of a reduced incidence of cough, and was not associated with the hypokalaemia or hyperuricaemia seen with hydrochlorothiazide in a study in patients aged ≥75 years. The drug has an adverse events profile similar to that of losartan potassium in patients with mild to moderate hypertension.

Conclusions: Once daily candesartan cilexetil is effective and well tolerated when used once daily (as monotherapy or in combination with other antihypertensive agents) in patients with mild, moderate or severe hypertension. Initially, however, the drug is likely to be used as an alternative to other agents in patients not responding to or intolerant of their current drug therapy.

Pharmacodynamic Properties

Candesartan cilexetil is completely converted to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a nonpeptide angiotensin II receptor blocker which binds selectively to and dissociates slowly from the angiotensin II receptor subtype 1 (AT1), thereby inhibiting the activity of angiotensin II at this receptor. The drug has no activity at the AT2 receptor subtype.

Consistent with angiotensin II receptor inhibition, single oral doses of candesartan cilexetil 1 to 8mg increased plasma renin activity and plasma angiotensin II levels in healthy volunteers and patients with hypertension. Both variables increased significantly within 4 hours of administration compared with placebo. In addition, single and multiple oral administration of the drug dose-dependently inhibited the pressor response to exogenous angiotensin II; ≈50% inhibition was observed 24 hours after an 8mg dose.

Results from animal studies suggest that candesartan cilexetil is effective in the prevention and regression of left ventricular (LV) hypertrophy. A preliminary clinical study indicated that the drug caused LV hypertrophy regression in patients with hypertension.

Candesartan cilexetil appears to preserve or improve renal function in patients with hypertension and to reduce urinary albumin excretion in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus and microalbuminuria.

Preclinical evidence suggests that candesartan cilexetil may have a cardioprotective effect after myocardial infarction.

The effects of candesartan cilexetil on stroke have not been clearly established, although the drug maintained cerebral blood flow despite reducing systemic blood pressure in 1 study. In stroke-prone spontaneously hypertensive rats, administration of oral candesartan cilexetil from 22 to 32 weeks of age reduced the incidence of stroke compared with untreated controls.

Candesartan cilexetil appears to improve insulin sensitivity in patients with essential hypertension and has no effects on glucose homeostasis or the serum lipid profile in patients with essential hypertension or coexisting type 2 diabetes mellitus.

Pharmacokinetic Properties

After tablet administration, candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption in the gastrointestinal tract. Peak plasma candesartan concentrations (Cmax) are reached ≈3 to 5 hours (tmax) after tablet administration and increase dose dependently. No drug accumulation occurs with repeated dosing of candesartan cilexetil. The bioavailability of an oral solution of candesartan is ≈42% and is not affected by food.

Volume of distribution is estimated to be 0.13 L/kg after intravenous administration; >99% of candesartan is plasma protein bound.

Candesartan is mainly eliminated unchanged although a small amount is metabolised by the isoenzyme cytochrome P450 (CYP)2C9 in human liver microsomes to the inactive metabolite CV 15959. The oral clearance of candesartan in 185 patients with hypertension who received candesartan cilexetil 2 to 16 mg/day for 28 days was calculated to be 14.07 L/h. The terminal elimination half-life (t½β) ranged from ≈9 to 13 hours and was independent of dose.

After oral administration, approximately 33% of the dose is recovered in urine and 68% in faeces as either candesartan or CV 15959. Over 90% of a dose is excreted within 72 hours of administration of an oral solution.

Cmax, area under the plasma concentration-time curve (AUC) and t½β values for candesartan after multiple dose administration increased by ≥40% in patients with varying degrees of renal impairment compared with healthy volunteers (p < 0.05); the pharmacokinetic profile of candesartan cilexetil was not significantly altered in patients with mild to moderate hepatic impairment.

Cmax values for candesartan were increased in elderly (≥65 years) compared with younger (≤40 years) volunteers after single or multiple dose administration of candesartan cilexetil.

Significant drug interactions are unlikely with candesartan because it does not inhibit CYP isoform-specific CYP activities.

Therapeutic Use

Dose-finding studies have shown that once daily candesartan cilexetil 8 to 32mg dose-dependently and effectively reduces blood pressure in most patients with mild to moderate essential hypertension irrespective of age. Furthermore, studies of ≤12 months’ duration have shown the drug to maintain its antihypertensive efficacy long term when administered in a flexible dosage range.

In a meta-analysis of 6 well controlled studies involving 1482 evaluable patients, the number of responders (patients whose sitting diastolic blood pressure was ≤90mm Hg or reduced by ≥10mm Hg after treatment) ranged from 35% with candesartan cilexetil 2mg to 55% with the 16mg dose. Ambulatory blood pressure monitoring showed that the placebo-corrected trough/peak ratios for candesartan cilexetil 8 to 16mg approached 80%.

The antihypertensive efficacy of candesartan cilexetil has been evaluated in a number of comparative trials of up to 12 weeks’ duration. An 8 mg/day dosage of the drug demonstrated blood pressure-lowering effects similar to those of enalapril 10mg, losartan potassium 50mg, amlodipine 5mg and hydrochlorothiazide 25mg after once daily administration. At 16 mg/day, candesartan cilexetil reduced trough diastolic blood pressure significantly more than losartan potassium 50 mg/day.

Candesartan cilexetil was effective when used as add-on therapy in patients with severe hypertension not responding to hydrochlorothiazide monotherapy and had additive antihypertensive effects when coadministered with amlodipine in patients with mild to moderate essential hypertension.

Candesartan cilexetil is also effective in the elderly and in patients with type 2 (non-insulin-dependent) diabetes mellitus.

Tolerability

Pooled tolerability data from placebo-controlled studies involving 4147 patients showed that the tolerability profile of candesartan cilexetil (8 or 16 mg/day) is not significantly different from that of placebo. 34.9 and 33.5% of patients in the respective groups reported at least 1 adverse event which may or may not have been related to treatment. The most commonly reported adverse event in both groups was headache; all events were of mild to moderate severity and were not dose related. Cough, which is an adverse event frequently reported with the use of ACE inhibitors, was reported in only 1.6% of patients receiving candesartan cilexetil compared with 1.1% receiving placebo.

Candesartan cilexetil is well tolerated in elderly (≥65 years) and younger (<65 years) patients and has not been associated with significant orthostatic effects in the elderly. Comparative studies have shown candesartan cilexetil to be better tolerated than enalapril, primarily because of a reduced incidence of cough. Furthermore, candesartan cilexetil was not associated with the hypokalaemia and hyperuricaemia seen with hydrochlorothiazide in a study in patients aged ≥75 years. In patients with mild to moderate hypertension, candesartan cilexetil had a tolerability profile similar to that of losartan potassium.

Candesartan cilexetil has no clinically significant effects on laboratory, biochemical or ECG parameters. However, minor and transient increases in liver enzyme activity have been reported in occasional patients.

Dosage and Administration

The initial and usual maintenance doses of candesartan cilexetil are 8 and 16mg once daily. US recommendations are that the dosage can be titrated within the range 8 to 32 mg/day according to response.

No initial dosage adjustment is necessary in the elderly, but patients with severe renal or hepatic impairment should start with candesartan cilexetil 4 mg/day. The drug is contraindicated in pregnancy.

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

    Karen J. McClellan & Karen L. Goa

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  1. Karen J. McClellan
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Correspondence to Karen J. McClellan.

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McClellan, K.J., Goa, K.L. Candesartan Cilexetil. Drugs 56, 847–869 (1998). https://doi.org/10.2165/00003495-199856050-00013

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