Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function.
OBJECTIVE
We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound.


METHODS
Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl x min(-1) x 1.73 m(-2), group B 30-60 ml x min(-1) x 1.73 m(-2) and group C 15-30 ml x min(-1) x 1.73 m(-2)).


RESULTS
Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUCinf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline.


CONCLUSIONS
Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment.
Buter
H
H
Department of Medicine, State University Hospital, Groningen, The Netherlands.
Navis
G Y
GY
Woittiez
A J
AJ
de Zeeuw
D
D
de Jong
P E
PE
D000328:Adult; D000804:Angiotensin II / Q000097:blood / Q000187:drug effects; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications*; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D012083:Renin / Q000097:blood / Q000187:drug effects; D013777:Tetrazoles / Q000097:blood
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D011355:Prodrugs; D013777:Tetrazoles; D000804:Angiotensin II; D012083:Renin; C077793:candesartan cilexetil; C081643:candesartan