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 ATI 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 C-max was 95.2 ng . ml(-1) in healthy subjects and 109 ng . ml(-1) in the patients. The AUC(0-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 C-max values were similar in both groups (112 vs 116 ng . ml(-1)); the AUG, 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 AUC(0-infinity) on day 1 was almost identical to the AUG, 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. Conclusion: Mild to moderate liver impairment has no clinically relevant effect on candesartan pharmacokinetics, and no dose adjustment is required for such patients.