Pharmacokinetics and safety of candesartan cilexetil in subjects with normal and impaired liver function.
OBJECTIVE
The influence of liver disease on the pharmacokinetics of candesartan, a long-acting selective AT1 subtype angiotensin II receptor antagonist was studied.


METHODS
Twelve healthy subjects and 12 patients with mild to moderate liver impairment received a single oral dose of 12 mg of candesartan cilexetil on day 1 and once-daily doses of 12 mg on days 3-7. The drug was taken before breakfast. Serial blood samples were collected for 48 h after the first and last administration on days 1 and 7. Serum was analyzed for unchanged candesartan by HPLC with UV detection.


RESULTS
The pharmacokinetic parameters on days 1 and 7 revealed no statistically significant influence of liver impairment on the pharmacokinetics of candesartan. Following single dose administration on day 1, the mean Cmax was 95.2 ng.ml-1 in healthy subjects and 109 ng.ml-1 in the patients. The AUC0-infinity was 909 ng.h.ml-1 in healthy volunteers and 1107 ng.h.ml-1 in patients and the elimination half-life was 9.3 h in healthy volunteers and 12 h in the patients. At steady state on day 7, mean Cmax values were similar in both groups (112 vs 116 ng.ml-1); the AUC tau was 880 ng.h.ml-1 in healthy subjects and 1080 ng.h.ml-1 in patients while the elimination half-life was 10 h in healthy subjects and 12 h in the patients with liver impairment. The ACU0-infinity on day 1 was almost identical to the AUC tau on day 7. A moderate drug accumulation of 20%, which does not require a dose adjustment, was observed following once-daily dosing in both groups. No serious or severe adverse events were reported.


CONCLUSIONS
Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients.
Hoogkamer
J F
JF
Takeda Euro Research and Development Centre, Frankfurt am Main, Germany.
Kleinbloesem
C H
CH
Ouwerkerk
M
M
Högemann
A
A
Nokhodian
A
A
Kirch
W
W
Weidekamm
E
E
D000328:Adult; D000368:Aged; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds; D005260:Female; D006801:Humans; D008107:Liver Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C081643:candesartan