Brand Name: Atacand
Generic Name: Candesartan
ATACAND (candesartan cilexetil) antagonizes angiotensin II by blocking the angiotensin type one (AT1) receptor. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system with effects that include vasoconstriction, stimulation of aldosterone secretion and renal reabsorption of sodium.
ATACAND, a prodrug, is rapidly converted to the active drug, candesartan, during absorption from the gastrointestinal tract.
Candesartan blocks the vasoconstrictor and aldosterone secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland.
Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but it plays no known role in cardiovascular homeostasis to date. Candesartan has a much greater affinity (>10 000 fold) for the AT1 receptor than for the AT2 receptor. The strong bond between candesartan and the AT1 receptor is a result of tight binding to and slow dissociation from the receptor.
Candesartan does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. In vitro studies indicate that cytochrome P450 isoenzyme CYP 2C9 is involved in the biotransformation of candesartan to its inactive metabolite. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The elimination half-life of candesartan is approximately 9 hours. After single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg. Candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing.
Following oral administration of candesartan cilexetil as a tablet, the absolute bioavailability of candesartan was estimated to be approximately 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food does not affect the bioavailability of candesartan after candesartan cilexetil administration.
Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan cilexetil is administered orally, about 26% of the dose is excreted as candesartan in urine. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an i.v. dose of 14C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.
The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan does cross the blood-brain barrier. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.
The plasma concentration of candesartan was higher in the elderly (≥65 years) (Cmax was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration.
No gender-related differences in the pharmacokinetics of candesartan have been observed.
In patients with mild to moderate renal impairment (Clcreat 31 to 60 mL/min/1.73 m2), Cmax and AUC of candesartan increased by 40 to 60% and 50 to 90%, respectively, but t1/2 was not altered, compared to patients with normal renal function (Clcreat >60 mL/min/1.73 m2) during repeated dosing. There was no drug accumulation in plasma in patients with mild to moderate renal impairment. The increases in Cmax and AUC in patients with severe renal impairment (Clcreat 15 to 30 mL/min/1.73 m2) were 40 to 60% and 110%, respectively. The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment, and these changes resulted in some accumulation in plasma. The pharmacokinetics of candesartan in patients undergoing hemodialysis were similar to those in patients with severe renal impairment
In patients with mild to moderate hepatic impairment, there was an increase in the AUC of candesartan of approximately 20%. There was no drug accumulation in plasma in these patients. In patients with moderate to severe hepatic impairment, the Cmax and AUC increased up to five times in a very small group administered a single dose of 16 mg candesartan
Pharmacodynamics: Candesartan inhibits the pressor effects of angiotensin II infusion in a dose dependent manner. After 1 week of once-daily dosing of 8 mg candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak (4-8 hours after dosing) with approximately 50% inhibition persisting at 24 hours.
Plasma concentrations of angiotensin I, angiotensin II, and plasma renin activity, increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects, hypertensive, and heart failure patients. A decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients.
Hypertension: ATACAND causes a dose-dependent reduction in arterial blood pressure. Systemic peripheral resistance is decreased, while heart rate, stroke volume and cardiac output are not significantly affected. No first dose hypotension was observed during controlled clinical trials with ATACAND.
Most of the antihypertensive effect was seen within 2 weeks of initial dosing, and the full effect in 4 weeks. With once-daily dosing, blood pressure effect was maintained over 24 hours with trough to peak ratios of blood pressure effect generally greater than 80%. Candesartan cilexetil had an additional blood pressure lowering effect when added to hydrochlorothiazide.
The antihypertensive effect was similar in men and women and in patients older and younger than 65. Candesartan was effective in reducing blood pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin population) than in Caucasians.
In long-term studies of up to 1 year, the antihypertensive effectiveness of candesartan cilexetil was maintained, and there was no rebound after abrupt withdrawal.
ATACAND reduces urinary albumin excretion in patients with type II diabetes mellitus, hypertension, and microalbuminuria. In a 12-week study of 161 mildly hypertensive patients with type II diabetes mellitus, ATACAND 8 to 16 mg had no effect on mean A1c.
Comparative Effects: The antihypertensive efficacy of candesartan cilexetil and losartan potassium have been compared at their once daily maximum doses, 32 mg and 100 mg, respectively, in patients with mild to moderate essential hypertension. Candesartan cilexetil lowered systolic and diastolic blood pressure by 2 to 3 mm Hg on average more than losartan potassium when measured at the time of either peak or trough effect. Both agents were well tolerated.
Heart Failure: In heart failure patients, ATACAND administration resulted in a dose-related increase in plasma renin activity and angiotensin II concentration, and a decrease in aldosterone levels.
The effects of ATACAND on mortality and hospitalization due to Congestive Heart Failure (CHF) were evaluated in two studies, CHARM-Alternative and CHARM-Added. These were multinational, placebo controlled, double blind studies in patients with New York Heart Association (NYHA) functional class II to class IV CHF. Class IV CHF was a baseline characteristic for only 3% of the patient population within each of these studies. CHARM-Alternative (n=2028) included patients with LVEF ≤40% not treated with ACE inhibitors because of intolerance. CHARM-Added (n=2548) was carried out in patients with LVEF ≤40% tolerant of ACE inhibitors and treated with ACE inhibitors. In these studies patients were randomised to receive either placebo or ATACAND in addition to standard therapy. ATACAND was titrated from 4 mg or 8 mg once daily to 32 mg once daily (mean 23 mg) or the highest tolerated dose. Patients were followed for up to 4 years, with a median of 40 months. Standard therapy included diuretics, β-blockers, ACE inhibitors, digoxin and spironolactone.
The primary composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with ATACAND in comparison with placebo in CHARM-Alternative (hazard ratio (HR) 0.77, 95% CI 0.67-0.89, p<0.001) and in CHARM-Added (HR 0.85, 95% CI 0.75-0.96, p=0.011). This corresponds to a relative risk reduction of 23% and 15% respectively. See Table 1
Table 1: ATACAND CHARM-Alternative: Primary Endpoint and its Components
| Endpoint (time to first event) |
ATACAND
(n=1013)
|
Placebo
(n=1015)
|
Hazard Ratio
(95% CI)
|
p-value
(logrank)
|
Relative Risk Reduction |
Absolute Risk Reduction |
| CV death or CHF hospitalisation |
334 |
406 |
0.77
(0.67–0.89)
|
<0.001 |
23% |
7.0% |
| CV death |
219 |
252 |
0.85
(0.71–1.02)
|
0.072 |
15% |
3.2% |
| CHF hospitalisation |
207 |
286 |
0.68
(0.57–0.81)
|
<0.001 |
32% |
7.7% |
Note: In CHARM-Alternative 14 patients needed to be treated for the duration of the study (median 34 months) to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure
|
