PHARMACOKINETICS OF CANDESARTAN AFTER SINGLE AND REPEATED DOSES OF CANDESARTAN CILEXETIL IN YOUNG AND ELDERLY HEALTHY-VOLUNTEERS

Candesartan cilexetil is rapidly and completely hydrolysed to the acti ve compound candesartan during absorption from the gastrointestinal tr act. Candesartan is a potent, long-acting, selective angiotensin II AT (1) receptor blocker. The pharmacokinetics of candesartan were investi gated after single and repeated once-daily doses of candesartan cilexe til in the dose range 2-16 mg in both younger (19-40 years) and elderl y (65-78 years) healthy volunteers in five studies. Blood pressure, he art rate, and hormones associated with the renin-angiotensin system, a nd 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, a nd during the last dosing interval after 1 week repeated once-daily ad ministration. Serum and plasma were analysed for candesartan cilexetil , candesartan and its inactive metabolite, CV-15959, as well as angiot ensin I and II, aldosterone, plasma renin activity (PRA) and angiotens in-converting enzyme (ACE) activity. The AUC and C-max of candesartan showed dose-proportional increases in the dose range of 2-16 mg candes artan cilexetil after both single and repeated once-daily tablet intak e, indicating linear pharmacokinetics in both younger and elderly heal thy subjects. The pharmacokinetics did not change on repeated dosing a nd, 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 t ablet intake was consistently approximately 4 h at all dose levels. Bo th C-max and AUC of candesartan were increased after single and repeat ed once-daily dosing in the elderly compared to younger subjects by ap proximately 50%. However, no accumulation after repeated once-daily do sing were seen in the elderly. The half-life of candesartan in the eld erly (9-12 h) was somewhat longer than in the younger healthy adult vo lunteers (approximately 9 h) and no gender-related differences in the disposition of candesartan were observed. Serum concentrations of CV-1 5959 were much lower than candesartan, and reached peak serum concentr ations later, about 4-9 h after dose intake. The elimination of CV-159 59 was somewhat stower than that of candesartan. Candesartan cilexetil , the prodrug to candesartan, was not measurable in serum. No differen ces 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 afte r 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 a dverse events were recorded, with 'headache' as the most commonly repo rted event, and no increase in the number of reported adverse events w as observed with higher doses of candesartan cilexetil. No clinically significant changes in respect to vital signs, physical examination, E CG, and clinical laboratory tests were observed.