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Pharmacology: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT1) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active substance, Candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an Angiotensin II Receptor Antagonist (AIIRA), selective for AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. The antagonism of the angiotensin II (AT1) receptors results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Pharmacokinetics: Absorption and distribution: Following oral administration, Candesartan cilexetil is converted to the active substance Candesartan. The absolute bioavailability of Candesartan is approximately 40% after an oral solution of Candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (Cmax) is reached 3 to 4 hours following tablet intake. The Candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range. No gender related differences in the pharmacokinetics of Candesartan have been observed. The area under the serum concentration versus time curve (AUC) of Candesartan is not significantly affected by food.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of Candesartan is 0.1 L/Kg. The bioavailability of Candesartan is not affected by food.
Biotransformation and elimination: Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). No interaction would be expected to occur with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of Candesartan is approximately 9 hours. There is no accumulation following multiple doses.
Total plasma clearance of Candesartan is about 0.37 mL/min/Kg, with a renal clearance of about 0.19 mL/min/Kg. The renal elimination of Candesartan is both by glomerular filtration and active tubular secretion. Following an oral dose of 14C-labelled Candesartan cilexetil, approximately 26% of the dose is excreted in the urine as Candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the feces as Candesartan and 10% as the inactive metabolite.
Pediatric population: In children aged 1 to <6 years, 10 children weighing 10 to <25 Kg received a single dose of 0.2 mg/Kg, oral suspension.
There was no correlation between Cmax and AUC with age or weight. No clearance data has been collected; therefore, the possibility of a correlation between clearance and weight/age in this population is unknown.
In children aged 6 to <17 years, there is no correlation between Cmax and AUC with age. However, weight seems to significantly correlate with Cmax (p=0.012) and AUC (p=0.011). The possibility of a correlation between clearance and weight/age in this population is unknown.
Children >6 years of age had exposure similar to adults given the same dose.
The pharmacokinetics of Candesartan cilexetil have not been investigated in pediatric patients <1 year of age.
