UMLS:C0004135 - FACTA Search

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Candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a potent, long-acting, selective angiotensin II AT1 receptor blocker. The pharmacokinetics of candesartan were investigated after single and repeated once-daily doses of candesartan cilexetil in the dose range 2-16 mg in both younger (19-40 years) and elderly (65-78 years) healthy volunteers in five studies. Blood pressure, heart rate, and hormones associated with the renin-angiotensin system, and safety of candesartan cilexetil administration were also assessed. Placebo comparisons were made in four studies. Frequent blood samples were collected after the first single dose of candesartan cilexetil, and during the last dosing interval after 1 week repeated once-daily administration. Serum and plasma were analysed for candesartan cilexetil, candesartan and its inactive metabolite, CV-15959, as well as angiotensin I and II, aldosterone, plasma renin activity (PRA) and angiotensin-converting enzyme (ACE) activity. The AUC and Cmax of candesartan showed dose-proportional increases in the dose range of 2-16 mg candesartan cilexetil after both single and repeated once-daily tablet intake, indicating linear pharmacokinetics in both younger and elderly healthy subjects. The pharmacokinetics did not change on repeated dosing and, as expected from the half-life of candesartan of approximately 9 h in younger subjects, there was almost no accumulation after repeated once-daily dosing. The time to peak candesartan concentrations after tablet intake was consistently approximately 4 h at all dose levels. Both Cmax and AUC of candesartan were increased after single and repeated once-daily dosing in the elderly compared to younger subjects by approximately 50%. However, no accumulation after repeated once-daily dosing were seen in the elderly. The half-life of candesartan in the elderly (9-12 h) was somewhat longer than in the younger healthy adult volunteers (approximately 9 h) and no gender-related differences in the disposition of candesartan were observed. Serum concentrations of CV-15959 were much lower than candesartan, and reached peak serum concentrations later, about 4-9 h after dose intake. The elimination of CV-15959 was somewhat slower than that of candesartan. Candesartan cilexetil, the prodrug to candesartan, was not measurable in serum. No differences in ACE activity or serum aldosterone concentrations were observed between subjects receiving candesartan cilexetil and placebo tablets. Plasma angiotensin I and II concentrations and PRA were augmented after single doses and further increased after 1 week repeated candesartan cilexetil dosing. Single and repeated doses of candesartan cilexetil were well tolerated in the younger and elderly volunteers. Only mild adverse events were recorded, with 'headache' as the most commonly reported event, and no increase in the number of reported adverse events was observed with higher doses of candesartan cilexetil. No clinically significant changes in respect to vital signs, physical examination, ECG, and clinical laboratory tests were observed.
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PMID:Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly healthy volunteers. 933 Oct

Candesartan is a potent and selective angiotensin II type 1 receptor blocker which binds tightly to and dissociates slowly from the AT1 receptor. It is administered orally as the prodrug candesartan cilexetil, which is rapidly and completely converted to the active compound, candesartan, during gastrointestinal absorption. In hypertensive patients, candesartan cilexetil dose-dependently lowers diastolic and systolic blood pressure (BP) over the 24-h dose interval and it maintains its antihypertensive effects in the long term. Clinical trials indicate that a once-daily dose of 4-16 mg provides a clinically relevant reduction in BP. The usual maintenance doses of candesartan cilexetil are expected to be 8 mg and 16 mg once-daily and dosage adjustment does not appear to be necessary in elderly patients or those with mild to moderate renal or hepatic impairment. Adverse events during treatment with candesartan cilexetil occur at a similar low incidence as with placebo and no dose-dependent events or adverse metabolic effects have been noted. As once-daily monotherapy, candesartan cilexetil 8 mg is as effective as enalapril 10-20 mg, amlodipine 5 mg or hydrochlorothiazide 25 mg, and candesartan cilexetil 16 mg is more effective than losartan 50 mg. The trough to peak ratio for the reduction in BP with candesartan cilexetil has been shown to be in the order of 80-100%, confirming the smooth 24-h BP-lowering profile of the drug. Combined treatment with candesartan cilexetil and hydrochlorothiazide or amlodipine provides an enhanced BP-lowering effect that is useful in patients with inadequate response to initial treatment after step-up titration. Candesartan cilexetil is similarly well tolerated as placebo, both when given as monotherapy, and in combination for example with hydrochlorothiazide. Candesartan cilexetil with its flexible dosage regimen therefore appears to offer an effective and well-tolerated alternative to other established agents in the treatment of a wide range of hypertensive patients.
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PMID:Candesartan cilexetil: a new, long-acting, effective angiotensin II type 1 receptor blocker. 933 Oct 18

Renal autoregulatory efficiency is compromised in angiotensin-II (AngII)-dependent Goldblatt hypertension. The current studies were performed to assess renal autoregulatory capability in AngII-infused hypertensive rats and to determine the effect of chronic candesartan cilexetil treatment on autoregulatory behavior. Rats received chronic infusion of AngII (60 ng/min) or vehicle via an osmotic minipump implanted subcutaneously in the dorsum of the neck. Selected rats received the novel AT1 receptor blocker candesartan cilexetil (1.0 mg/kg per d) in the drinking water. Systolic BP averaged 118+/-1 mmHg (n=34) before pump implantation. Chronic AngII infusion for 6 d increased arterial pressure to 151+/-4 mmHg. Candesartan cilexetil administration prevented the AngII-dependent increase in systolic BP. Microvascular autoregulation experiments were performed in vitro using the blood-perfused juxtamedullary nephron technique combined with videomicroscopy. Renal perfusion pressure was set at 100 mmHg during the control period before being decreased to 65 mmHg. Afferent arteriolar diameter was measured continuously as the perfusion pressure was increased from 65 mmHg to 170 mmHg in 15-mmHg increments. Afferent arteriolar diameter in sham-treated rats was 120% of control at a perfusion pressure of 65 mmHg and decreased to 76% of the control diameter at 170 mmHg (n=6). This behavior is consistent with normal autoregulatory behavior. Arterioles from rats receiving chronic infusion of AngII exhibited compromised renal microvascular autoregulatory efficiency. Afferent arteriolar diameter in AngII-treated kidneys varied from 103 to 100% (n=6) of the control diameter over the same pressure range of 65 to 170 mmHg. This blunting of autoregulatory behavior was prevented by AT1 receptor blockade. In animals receiving AngII + candesartan cilexetil, stepwise changes in perfusion pressure elicited changes in afferent arteriolar diameter between 120 and 84% after 6 d of treatment (n=6). These data suggest that chronic elevations in circulating AngII and/or the associated increase in arterial pressure impairs renal autoregulatory capability. Furthermore, inhibition of AT1 receptors with candesartan cilexetil provides protection against AngII-mediated increases in arterial pressure and prevents the associated deterioration of renal autoregulatory responsiveness.
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PMID:Candesartan cilexetil protects against loss of autoregulatory efficiency in angiotensin II-infused rats. 989 60

Current research on angiotensin II AT1-receptor antagonists (AIIRAs) and selected studies presented at the recent symposium held in Amsterdam, The Netherlands, on 6 June 1998, titled 'Angiotensin II Receptor Antagonists are NOT all the Same' are reviewed. AIIRAs offer a number of potential advantages over alternative antihypertensive agents acting via the renin-angiotensin-aldosterone system. They combine blood pressure-lowering effects at least equivalent to those of angiotensin-converting enzyme (ACE) inhibitors, coupled with placebo-like tolerability. Candesartan cilexetil is a novel AIIRA that has demonstrated clinical efficacy superior to losartan, has a sustained duration of action over 24 hours (trough:peak ratio close to 100%) and is well tolerated in patients with essential hypertension. Candesartan cilexetil has a rapid onset of action (approximately 80% of total blood pressure reduction within the first 2 weeks) and dose-dependent effects on blood pressure, is comparable in efficacy to a number of classes of antihypertensives, and is effective in combination therapy (eg, with hydrochlorothiazide and amlodipine). This favourable profile may be due in part to the highly selective, tight binding to and slow dissociation of candesartan from the AT1 receptor. Preliminary studies suggest that candesartan cilexetil also protects end organs (kidney, heart, vasculature, and brain) beyond blood pressure control.
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PMID:Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists. 1007 15

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several animal models of hypertension. In spontaneously hypertensive rats, the duration of the antihypertensive effect of candesartan cilexetil was compared to those of losartan, valsartan, eprosartan, and irbesartan at the same degree of maximal blood pressure reduction. A single oral dose of candesartan cilexetil at 0.3 mg/kg reduced maximal blood pressure by about 25 mm Hg, and the antihypertensive effect of candesartan cilexetil lasted the longest, continuing for more than 1 week, without an effect on circadian rhythm. In a rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II. This inhibitory mode was different from that of other angiotensin II-receptor antagonists, and showed a shift to the right in the angiotensin II-induced contraction curve and/or a small depression of the maximal response. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The dissociation rate of tritiated candesartan binding (t1/2 = 66 min) was five times slower than that of radiolabelled angiotensin II binding (t1/2 = 12 min). The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from angiotensin II AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.
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PMID:Pharmacologic properties of candesartan cilexetil--possible mechanisms of long-acting antihypertensive action. 1007 25

Candesartan cilexetil has shown potent and long-lasting antihypertensive effects in clinical trials and in several hypertensive animal models. In rabbit aortic preparation, candesartan, active form of candesartan cilexetil, decreased the maximal contractile response of angiotensin II (insurmountable inhibition). This inhibitory mode was different from that of other angiotensin II receptor blockers, and showed a shift to the right in the angiotensin II-induced contraction curve. In kinetic studies using bovine adrenal cortical membrane and tritiated candesartan, both receptor association and dissociation were found to be slow. The insurmountable inhibition of candesartan in vascular contraction is the result of its tight binding and slow dissociation from AT1 receptors. These characteristics are related to the potency and long duration of action in candesartan cilexetil.
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PMID:[Pharmacological profiles of candesartan cilexetil (TCV-116)]. 1036 46

Blockade of the action of angiotensin ii (AII) has long been a target for development of novel antihypertensive agents. We recently discovered a novel class of potent non-peptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable antagonist selective in the angiotensin II type-I receptor (AT1). Structure-activity relationship (SAR) studies revealed that the adjacent arrangement of a lipophilic substituent, a tetrazolylbiphenylmethyl moiety and a carboxyl group was the important structural requirement for potent AII antagonistic activity. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. To improve bioavailability of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that, when given once-daily to patients, provides effective 24 hr blood pressure control.
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PMID:A new class of diacidic nonpeptide angiotensin II receptor antagonists: candesartan cilexetil. 1053 6

The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a longlasting binding to the human AT1-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose intake. After a 4-week placebo lead-in period, 268 patients with sitting diastolic BP 95 to 110 mm Hg and mean awake ambulatory DBP > or =85 mm Hg were randomized to receive either 8 mg of candesartan, 50 mg of losartan, or placebo for a 4-week period. Thereafter, the doses were doubled in all patients for an additional 4-week period. Ambulatory BP monitoring was performed for 36 h after dosing and clinic BP measured 48 h after dosing. Candesartan cilexetil (16 mg) reduced ABP to a significantly greater extent than 100 mg of losartan, particularly for systolic ABP during daytime (P<.05), nighttime (P<.05), and 24-h (P<.01) periods, systolic (P<.01) and diastolic (P<.05) ABP between 0 and 36 h, and both systolic (P<.001) and diastolic (P<0.001) ABP during the day of a missed dose. Clinic BP at 48 h after dosing was significantly reduced exclusively with 16 mg of candesartan. The differences in BP reduction between 8 mg of candesartan and 50 mg of losartan were statistically significant for systolic ABP during daytime (P<.01), nighttime (P<.05), 24-h (P<.01), 0 to 36 h (P<.05) and during the day of missed dose (P<.05). Moreover, although losartan did not significantly reduce ambulatory BP in a dose-related manner, ambulatory systolic and diastolic BP reductions with 16 mg of candesartan were significantly greater (P<.01 and <.001) than those seen with 8 mg of candesartan during every period at the ABP supporting a dose-response relationship. In conclusion, this forced titration study in ambulatory hypertensive patients demonstrates that candesartan cilexetil provides significant dose-dependent reduction in both clinic and ambulatory BP in doses ranging from 8 to 16 mg once daily. Furthermore, candesartan cilexetil is superior to losartan in reducing systolic ABP and in controlling both systolic and diastolic ABP on the day of a missed dose. The differences observed between both agents are most likely attributable to a tighter binding to, and a slower dissociation from, the receptor binding site with candesartan cilexetil.
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PMID:A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebo-controlled, forced titration study. Candesartan/Losartan study investigators. 1061 80

The renin-angiotensin system plays a central role in the regulation of blood pressure through its primary effector hormone angiotensin II. Studies conducted nearly 30 years ago with peptidic angiotensin II receptor blockers (ARB) suggested that disruption of the renin-angiotensin system offered considerable promise for the treatment of hypertension as well as heart failure. This promise was initially realized with the advent of angiotensin converting enzyme inhibitors, and more recently with nonpeptidic ARB that selectively antagonize the AT1-angiotensin receptor subtype. The potent and long-acting agent candesartan cilexetil illustrates how these new ARB fulfill the promises suggested by the early studies. Candesartan cilexetil provides a clinically relevant, dose-dependent reduction in diastolic and systolic blood pressure at doses of 4 to 16 mg once daily in patients with mild to moderate hypertension. Recent studies suggest that further blood pressure lowering is obtained with a 32-mg once daily dose. In comparative clinical trials, 8 mg of candesartan cilexetil and 10 to 20 mg of enalapril provided comparable antihypertensive effects. The safety and tolerability profile of candesartan cilexetil is comparable to placebo. Notably, this agent does not produce the dry, nonproductive cough that often limits use of angiotensin converting enzyme inhibitors, nor does it cause side effects that limit other antihypertensive drug classes. On the basis of the results of initial clinical studies, ARB also possess cardioprotective and renoprotective properties that promise to expand the role that these new agents will play in treating cardiovascular disorders.
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PMID:Update on the clinical pharmacology of candesartan cilexetil. 1067 85

Angiotensin II receptor blockers (ARBs) represent a new class of effective and well tolerated orally active antihypertensive agents. Recent clinical trials have shown the added benefits of ARBs in hypertensive patients (reduction in left ventricular hypertrophy, improvement in diastolic function, decrease in ventricular arrhythmias, reduction in microalbuminuria, and improvement in renal function), and cardioprotective effect in patients with heart failure. Several large long-term studies are in progress to assess the beneficial effects of ARBs on cardiac hypertrophy, renal function, and cardiovascular and cerebrovascular morbidity and mortality in hypertensive patients with or without diabetes mellitus, and the value of these drugs in patients with heart disease and diabetic nephropathy. The ARBs specifically block the interaction of angiotensin II at the AT1 receptor, thereby relaxing smooth muscle, increasing salt and water excretion, reducing plasma volume, and decreasing cellular hypertrophy. These agents exert their blood pressure-lowering effect mainly by reducing peripheral vascular resistance usually without a rise in heart rate. Most of the commercially available ARBs control blood pressure for 24 h after once daily dosing. Sustained efficacy of blood pressure control, without any evidence of tachyphylaxis, has been demonstrated after long-term administration (3 years) of some of the ARBs. The efficacy of ARBs is similar to that of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors or calcium channel blockers in patients with similar degree of hypertension. Higher daily doses, dietary salt restriction, and concomitant diuretic or ACE inhibitor administration amplify the antihypertensive effect of ARBs. The ARBs have a low incidence of adverse effects (headache, upper respiratory infection, back pain, muscle cramps, fatigue and dizziness), even in the elderly patients. After the approval of losartan, five other ARBs (candesartan cilexetil, eprosartan, irbesartan, telmisartan, and valsartan) and three combinations with hydrochlorothiazide (irbesartan, losartan and valsartan) have been approved as antihypertensive agents, and some 28 compounds are in various stages of development. The ARBs are non-peptide compounds with varied structures; some (candesartan, losartan, irbesartan, and valsartan) have a common tetrazolo-biphenyl structure. Except for irbesartan, all active ARBs have a carboxylic acid group. Candesartan cilexetil is a prodrug, while losartan has a metabolite (EXP3174) which is more active than the parent drug. No other metabolites of ARBs contribute significantly to the antihypertensive effect. The variation in the molecular structure of the ARBs results in differences in the binding affinity to the receptor and pharmacokinetic profiles. The differences observed in lipid solubility, absorption/distribution, plasma protein binding, bioavailability, biotransformation, plasma half-life, and systemic elimination influence the time of onset, duration of action, and efficacy of the ARBs. On the basis of the daily mg dose, the antihypertensive potency of the ARBs follows the sequence: candesartan cilexetil > telmisartan approximately = losartan > irbesartan approximately = valsartan > eprosartan. After oral administration, the ARBs are rapidly absorbed (time for peak plasma levels = 0.5-4 h) but they have a wide range of bioavailability (from a low of 13% for eprosartan to a high of 60-80% for irbesartan); food does not influence the bioavailability, except for valsartan (a reduction of 40-50%) and eprosartan (increase). A limited dose-peak plasma levels/areas under the plasma level-time curve proportionality is observed for some of the ARBs. Most of these drugs have high plasma protein binding (95-100%); irbesartan has the lowest binding among the group (90%). The steady-state volumes of distribution vary from a low of 9 L (candesartan) to a high of 500 L (telmisartan). (ABSTRACT TRUNCATE
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PMID:Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. 1085 85

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