Easthope SE, Jarvis B

Easthope SE, Jarvis B

Candesartan cilexetil - An update of its use in essential hypertension

Drugs 2002;62 (8);1253-87

The use of candesartan cilexetil in the treatment of essential hypertension is discussed with reference to pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, dosage, administration and hypertension management. It is mentioned that candesartan cilexetil is an orally administered non-peptide angiotensin II type 1 (AT1) receptor antagonist. Candesartan has been shown to be more powerful than EXP-3174 (the active metabolite of losartan), eprosartan, irbesartan and valsartan at blocking angiotensin II binding to human AT1 receptors in vitro. Candesartan was found to cross the blood brain barrier and induced a decrease in the maximal contractile response to angiotensin II in animal studies. Receptor inhibition in vascular preparations by candesartan was reversed by losartan. Dissociation of candesartan from the AT1 receptor was found to take a prolonged period in vitro. Pretreatment with candesartan suppressed accumulation of inositol triphosphate in the cells by 94% in vitro. The response to angiotensin II was reduced by candesartan cilexetil to a similar level as irbesartan and to a similar or greater extent than by losartan. The apparent dose needed for a 2-fold shift in the angiotensin II dose-response curve was found to be 1.94 mg 24 h after administration in 1 trial and 6 mg in another trial. The greatest response to single oral doses of candesartan cilexetil 4-16 mg occurred approximately 6-9 h after administration and effects lasted for over 24 h, while multiple doses improved the response by 33% more. Candesartan decreased plasminogen activator inhibitor-1 (PAI-1) levels in animal and in vitro studies but increased levels in postmenopausal women. Left ventricular (LV) mass, LV mass index and blood pressure (BP) are decreased by candesartan, which may induce regression of LV hypertrophy. Renal vascular resistance, glomerular filtration rate, renal plasma flow, filtration fraction and renal blood flow are all improved by candesartan cilexetil. Candesartan improved urinary albumin levels and urinary protein excretion but no effect on potassium, sodium and uric acid excretion has been found. A beneficial effect on the vasoconstrictive response to N(G)-monomethyl-L-arginine (L-NMMA) and a reduction in vasodilatory response to the endothelin A/B receptor antagonist TAK 044 and in circulating endothelin-1 concentrations occurred with candesartan cilexetil treatment. Oral candesartan cilexetil is absorbed through the gastrointestinal wall and hydrolysed by carboxylesterase to candesartan. The absolute oral bioavailability of candesartan (approximately 15%) and AUC are not altered by the presence of food while Cmax and Tmax values are. Peak Cmax values ranged between 27.6 mcg/l in young healthy volunteers and 244 mcg/l in renally impaired patients on dialysis and were dose-related. Tmax values for oral candesartan cilexetil 4-16 mg were approximately 3-5 h after administration. AUC was dose-dependent and ranged between approximately 250 and 1100 mcg/h/l. It is noted that candesartan is over 99% bound to plasma proteins, with a low volume of distribution after iv administration. Candesartan is eliminated in the urine (33%) and feces (68%) with approximately 75% eliminated as candesartan and 25% as an inactive metabolite. The elimination half-life was approximately 9-13 h and was dose-independent. Clearance rates of 0.022 l/h/kg have been recorded in healthy volunteers after iv administration. Renal clearance of 0.642 l/h occurred with a single oral dose of candesartan cilexetil 8 mg in healthy subjects and clearance of 14.07 l/h occurred in hypertensive patients given 2-16 mg/day. Hypertensive, renally impaired patients had greater AUC, Cmax and elimination half-life values with candesartan than healthy patients. Hemodialysis did not affect elimination of candesartan. The pharmacokinetics of candesartan were not affected by the occurrence of mild-to-moderate hepatic impairment but AUC and Cmax were significantly increased in patients with moderate to severe hepatic impairment. The coadministration of candesartan and hydrochlorothiazide, sustained-release nifedipine, glibenclamide, digoxin, ethinylestradiol, levonorgestrel or warfarin did not affect the pharmacokinetics of the drugs, however, coadministration of lithium and candesartan increased lithium concentrations. Candesartan cilexetil (8-32 mg/day) was found to be more effective than losartan in treating hypertension and controlling SBP and DBP and pulse pressure, with a longer duration of action. Losartan or candesartan with hydrochlorothiazide were found to induce greater decreases in trough seated DBP than candesartan or losartan alone. Candesartan was more effective in reducing BP at higher doses. Treatment with candesartan 8-16 mg/day was found to induce similar reductions in SBP and DBP as achieved with irbesartan, losartan or valsartan but induced greater reductions than

enalapril. Patients who received candesartan and enalapril had similar mean ambulatory BP 24 h. Less patients receiving candesartan required a dose increase. Candesartan was associated with greater reductions in DBP and SBP, but with similar health-related quality of life, than ACE inhibitors and hydrochlorothiazide while the response rate with candesartan was greater than with ACE inhibitors but similar to that of hydrochlorothiazide. BP reductions were similar with candesartan cilexetil and amlodipine in patients with mild or mild-to-moderate hypertension but a greater decrease in SBP occurred with candesartan cilexetil plus amlodipine. Comparable decreases in SBP and DBP were seen with candesartan, felodipine and lisinopril, while an additive effect was seen when candesartan and felodipine or lisinopril were used together. The urinary albumin to creatinine ratio was decreased similarly by candesartan and lisinopril. Candesartan was found to be efficacious as an add-on therapy and as a long-term therapy. In various trials, candesartan was found to be effective in patients with moderate to severe hypertension, elderly patients, patients with NIDDM, renal failure, stroke and in hypertensive patients of ethnic groups. Candesartan has been found to be well-tolerated in clinical trials, with adverse events including back pain, headache, cough, increases in liver enzyme concentrations and hypotension. The recommended doses of candesartan range between 16-32 mg/day,in the USA and 4-16 mg/day in Europe. A fixed dose product comprising candesartan cilexetil/hydrochlorothiazide is also available. Candesartan should not be given to pregnant or lactating women and should be given with caution to patients with renal artery stenosis or volume- and/or salt-depleted

patients. The authors conclude that candesartan cilexetil is an effective antihypertensive therapy with renoprotective effects.

Melian EB, Jarvis B

Candesartan cilexetil plus hydrochlorothiazide combination - A review of its use in hypertension

Drugs 2002; 62(5):787-816

This review discusses the pharmacodynamic properties, pharmacokinetic properties, the therapeutic use, the tolerability, the dosage and administration of candesartan cilexetil and hydrochlorothiazide as well as the role of both agents combined in the treatment of patients with hypertension. In the introduction, it is mentioned that the renin-angiotensin system (RAS) is inhibited by candesartan. Candesartan cilexetil is a nonpeptide angiotensin II receptor blocker that binds with high specificity to angiotensin subtype 1 (AT1) but not to angiotensin subtype 2 (AT2) receptors. It is rapidly and completely converted to candesartan, the active compound, during absorption from the upper gastrointestinal tract. Regarding the pharmacodynamic properties, it was shown that plasma renin activity and plasma angiotensin II concentration were dose-dependently increased by oral candesartan cilexetil 1-8 mg (single dose). The increase was accentuated with repeated dose, and was significant and long-lasting (present 24 h after drug administration). In healthy volunteers, it was shown that 24 h after administration candesartan had an angiotensin II inhibiting activity per mg stronger than that of losartan, irbesartan, telmisartan and valsartan. The inhibitory effect of candesartan cilexetil also appears to be of longer duration than that of losartan. Studies comparing irbesartan 150 mg with candesartan cilexetil 8 mg showed, in vivo, a similar angiotensin II inhibiting activity after administration of single (1 day) or multiple (87 days) doses. Ex vivo, irbesartan 150 mg appeared to induce a greater AT1 blockade than candesartan cilexetil 8 mg. In AT1 receptor-transfected Chinese Hamster Ovary Cells (CHO-hAT1), the half-life of candesartan was 120 min. The authors state that "candesartans slow dissociation from and rebinding to AT1 receptors may explain its long-lasting effect in clinical setting". Other studies have shown that among patients receiving candesartan cilexetil 16 mg/day, 48 h after administration, significant reductions of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were observed despite undetectable plasma concentrations of candesartan. It has been demonstrated that in 15 patients with hypertension, candesartan cilexetil improved tonic nitric oxide (NO) release and reduced the vasoconstrictive effect of endogenous endothelin-1 (ET-1). Candesartan cilexetil 8 or 16 mg/day reduced plasma ET-1 concentration from baseline after 2 and 12 months (2.49, 1.61 and 0.72 ng/l respectively). Furthermore, after 2 and 12 months of treatment, candesartan cilexetil enhanced vasoconstriction to intra-arterial Ng-monomethyl-L-arginine. Several studies conducted with hypertensive patients treated with candesartan cilexetil showed a reduction of the left ventricular (LV) mass, beneficial effects on diastolic function, a reduction of LV hypertrophy as well as forearm vascular resistance at rest and after ischemia, an improvement in mean diastolic time and peak velocity filling. A reduction of LV mass index, and a deceleration time and isovolumetric relaxation time were observed with long term (52 weeks) candesartan cilexetil 16 mg once daily. In hypertensive patients with concomitant NIDDM and/or renal impairment, candesartan cilexetil improves/preserves renal function and reduces proteinuria without affecting urinary sodium, potassium, or uric acid excretion. Studies showed that candesartan 4-8 mg/day for 2 weeks or 16 mg (single dose) given to hypertensive patients induced a significant reduction of the the renal vascular resistance and filtration fraction as well as a significant increase of renal plasma flow and blood flow. Some studies found that the glomerular filtration rate was affected by candesartan cilexetil but others did not. The Candesartan And Lisinopril Microalbuminuria (CALM) study showed that candesartan reduced the urinary albumin to creatinine ratio in hypertensive patients with NIDDM. Another study also showed an increase in creatinine clearance. The effect of candesartan cilexetil on plasminogen activator inhibitor 1 (PAI-1) is unclear. In vitro experiments on animal and human models showed that candesartan induced a reduction of PAI-1 concentrations but these results were not confirmed by other studies. A reduction of aortic and cardiac PAI-1 expression was observed following an infusion of candesartan cilexetil in spontaneously hypertensive rats receiving angiotensin II infusion. Studies have shown that in adipocytes not challenged with angiotensin II, candesartan cilexetil reduced PAI-1 release and in postmenopausal women treated with candesartan cilexetil, a significant increase in the plasma concentration of PAI-1 was noted. The section discussing the pharmacodynamic properties of hydrochlorothiazide reports studies which showed that, regarding LV mass reduction, hydrochlorothiazide treatment was similar to captopril and atenolol treatment while, regarding reduction in left atrial size, hydrochlorothiazide was superior to diltiazem, clonidine, prazosin, captopril and atenolol treatment. Regarding the pharmacokinetics of the combination of candesartan cilexetil and hydrochlorothiazide, it was found that the peak plasma concentration (Cmax), Tmax or elimination half-life (t1/2) of hydrochlorothiazide were not affected by the coadministration of candesartan. However, candesartan did significantly decrease the AUC of the serum concentration-time values of hydrochlorothiazide. On the other hand, coadministration of hydrochlorothiazide increased the bioavailability of candesartan by 20% and Cmax by 23%, but tmax, t1/2 and mean residence time were not affected. In the section discussing the pharmacokinetics of candesartan cilexetil, it is mentioned that in healthy volunteers and various patient groups, candesartan cilexetil is rapidly and completely hydrolyzed to the active compound candesartan during absorption from the gastrointestinal tract. Cmax occurred 3-5 h after oral administration and increased in a dose-related manner. Accumulation of candesartan was not observed after repeated administration of candesartan cilexetil and its bioavailability was 42% of that seen in iv administration. In hypertensive patients, total plasma clearance of candesartan was 14.07 l/h and in healthy volunteers it was 0.25 and 0.20 l/h/kg depending on the dosage. The t1/2 ranged from 9-13 h and was dose-independent. In an elderly population (aged > = 65 years), candesartan cilexetil Cmax and AUC values were higher by 50% and 80%, respectively and the t1/2 was slightly longer. In comparison with hypertensive patients with normal kidney function, substantial increases in Cmax and AUC after repeated doses of candesartan cilexetil were reported in those patients with renal impairment. For patients with severe hepatic impairment, it is recommended to reduce the initial dosage of candesartan cilexetil. Indeed, in patients with severe hepatic impairment an increase in AUC and Cmax by 78% and 64%, respectively have been reported. Concerning potential drug interactions, the authors mention that "since candesartan is poorly metabolized by CYP system enzymes, inhibitors and inducers of these enzymes are not likely to interact with candesartan". In the studies assessing the therapeutic efficacy of the combination hydrochlorothiazide-candesartan cilexetil, the combination therapy was given once daily, as a fixed combination tablet or as separate tablets of the drugs. It appears from several studies that in the treatment of patients with mild to moderate hypertension, the combination therapy candesartan cilexetil (4, 8, or 16 mg) plus hydrochlorothiazide (12.5 or 25 mg) was effective and induced greater reductions of blood pressure than equivalent monotherapy with either drug. Several experiments conducted with patients who previously failed to respond to hydrochlorothiazide monotherapy showed that these patients responded to add-on candesartan cilexetil. Several clinical trials showed that the fixed combination candesartan cilexetil (16 mg)/hydrochlorothiazide (12.5 mg) was more efficacious than the combination of losartan (50 mg) and hydrochlorothiazide (12.5 mg) in the treatment of mild to severe hypertension; and it was as efficacious as the combination of lisinopril (10 mg) and hydrochlorothiazide (12.5 mg) in patients with mild to moderate hypertension. Regarding the tolerability of the combination, the most common adverse events reported are headache, back pain, dizziness, respiratory tract infection, influenza-like symptoms and in rare cases hypokalemia. The combination therapy of hydrochlorothiazide with either candesartan cilexetil, lisinopril or losartan are all well tolerated. However, comparing lisinopril and candesartan cilexetil, it appears that the incidence of at least 1 adverse event and cough was higher among the patients treated with lisinopril/hydrochlorothiazide. Regarding the dosage and administration of the combination of candesartan cilexetil and hydrochlorothiazide, the authors mention that this combination is recommended for the treatment of patients with hypertension who do not achieve blood pressure (BP) control after receiving monotherapy with either drug. Usually, it is advised to start with a low dose and to increase it slowly depending on the clinical effect. As monotherapy, candesartan cilexetil recommended daily doses are 8-32 mg in United States, but the maximum is only 16 mg in Europe. For hydrochlorothiazide, the daily doses are 12-50 mg. In patients whose BP is not controlled with candesartan cilexetil 32 mg, the combination of candesartan cilexetil 32 mg and hydrochlorothiazide can be administered, and those patients who do not respond to candesartan cilexetil 16 mg can receive the combination of candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg. For patients with renal impairment, the combination of candesartan cilexetil of hydrochlorothiazide can be administered only if the patient's creatinine clearance is > = 30 l/h. For patients with hepatic deficiency, this combination should be administered carefully and it is even recommended to reduce the initial dose of candesartan cilexetil. This combination can be prescribed with other hypertensive agents and administered with or without food but it should not be administered to pregnant women. The authors conclude that the candesartan cilexetil/hydrochlorothiazide combination is an effective treatment for patients with hypertension, is significantly more efficacious than either agent alone and has an excellent adverse event profile.

Gleiter CH, Morike KE

Clinical pharmacokinetics of candesartan

Clinical Pharmacokinetics 2002 ;41(1):7-17

In this review recently published data on the clinical pharmacokinetics of candesartan are presented. Candesartan cilexetil is the esterified prodrug of candesartan. The following characteristic kinetic data were observed after investigations in healthy volunteers. Candesartan cilexetil is rapidly and totally hydrolysed enzymatically to candesartan during absorption in the gastrointestinal tract following oral administration. The oral bioavailability in humans is about 40%. Plasma concentrations of candesartan cilexetil are not detected after oral administration of the drug. The active metabolite appears after a mean lag-time of 1 h after a single dose as well as after 8 consecutive days of treatment. Cmax was reached between 3.5 and 6 h. AUC and Cmax values increased in proportion to the dose after the 3 lowest doses (1, 2 and 4 mg once daily). In general the plasma protein binding of candesartan in humans is more than 99%. It also appears that candesartan is unable to penetrate blood cells. A mass balance study showed that when C-14 candesartan was administered to healthy volunteers as a single dose, 33% of the radioactivity was discovered in the urine and 68% in the faeces. Following both iv and oral administration, it was found that more than 90% of total radioactivity was excreted within 72 h of administration. Therefore a great deal of candesartan cilexetil is not absorbed and any candesartan that reaches the systemic circulation is mainly excreted by the kidneys. In vitro studies have shown that candesartan failed to illustrate any affinity for any of the clinically relevant cytochrome enzymes. In healthy volunteers a 1-compartment model was used to show a mono-exponential decline of candesartan plasma concentrations with a half-life of 3.5 h (day 1) and 4 h (day 8). Other studies are also examined and the authors believe that the terminal elimination half-life of candesartan may have been underestimated. When candesartan was administered iv to healthy volunteers the total clearance was 0.0222 l/h/kg. In volunteers (aged 18-50 years) after a single oral dose of candesartan cilexetil 8 mg, the renal clearance was 0.64 l/h. No clinically significant effects of food on therapy with candesartan cilexetil are documented. Tmax was decreased and Cmax increased in healthy volunteers after taking candesartan 8 mg in the fed state, whilst AUC remained unaffected. Candesartan cilexetil can be administered irrespective of meals. Candesartan cilexetil had no pharmacodynamic or pharmacokinetic interactions with nifedipine, glibenclamide, digoxin, ethinylestradiol/levonorgestrel, warfarin or hydrochlorothiazide in a series of drug-drug interaction studies. The inhibitory effect of candesartan on systolic blood pressure response to angiotensin II was long lasting and dose-related. The study by Azizi et al., where candesartan 8 and 12 mg/day was compared with losartan showed that a dose-response relationship existed for both doses of candesartan. The clinically effective dosage range of between 8 and 32 mg/day was established following several dose-finding studies. The maximum antihypertensive effect is reached after an intake of the drug for about 1 week. AUC/dose corrected for body mass was not different between males and females. Pharmacokinetic parameters are similar in Black and in non-Black populations. When candesartan was administered to healthy young and elderly volunteers at dosages of 2 to 16 mg/day it resulted in higher Cmax and AUC in the elderly population but drug accumulations did not occur. In a double-blind study oral doses of candesartan 2, 4, 8, 12 and 16 mg/day in 232 patients with hypertension aged between 28 and 69 years it was shown that age of the hypertensive patient population did have an influence on the distribution and elimination of the drug. Evaluation of the studies to date leads scientists to believe that candesartan has an elimination half-life longer than 8 hours. Part of this review examines disease and the pharmacokinetics candesartan in patients with hypertension and with normal to severely impaired renal function. Pharmacokinetics and pharmacodynamics of candesartan 8 mg/day were studied. Serum concentrations at trough were significantly higher in patients with severely impaired renal function compared with those with normal kidney function. Subsequent analysis revealed the absence of clinically relevant accumulation of candesartan at the 8 mg dose. It was also noticed that a considerable negative correlation between AUC and glomerular filtration rate (GFR) occurred. An accumulation of candesartan was found with multiple doses of candesartan 12 mg/day where the drug was administered to patients with renal impairment and hypertension. In patients with renal impairment the mean Cmax, AUC and elimination half-life values increased. The accumulation factor was 1.71 in this study and a similar sub-study found the accumulation factor to be 1.44 for candesartan 8 mg/day. Analysis by Pfister et al. illustrated that no significant elimination of candesartan occurs with hemodialysis. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Candesartan is mainly excreted unchanged through renal and biliary routes. Evidence thus far suggests that any state of hypertension by itself is unable to change the pharmacokinetics of candesartan. The authors conclude that candesartan cilexetil appears to be a reasonably easy to handle drug for patients with hypertension who do not tolerate ACE inhibitors.