PHARMACOKINETICS AND SAFETY OF CANDESARTAN CILEXETIL IN SUBJECTS WITHNORMAL AND IMPAIRED LIVER-FUNCTION

Objective: The influence of liver disease on the pharmacokinetics of c andesartan, a long-acting selective ATI subtype angiotensin II recepto r antagonist was studied. Methods: Twelve healthy subjects and 12 pati ents with mild to moderate liver impairment received a single oral dos e of 12 mg of candesartan cilexetil on day 1 and once-daily doses of 1 2 mg on days 3-7. The drug was taken before breakfast. Serial blood sa mples 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 a nd 7 revealed no statistically significant influence of liver impairme nt on the pharmacokinetics of candesartan. Following single dose admin istration on day 1, the mean C-max was 95.2 ng . ml(-1) in healthy sub jects 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 patient s 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 s imilar 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 almo st identical to the AUG, on day 7. A moderate drug accumulation of 20% , which does not require a dose adjustment, was observed following onc e-daily dosing in both groups. No serious or severe adverse events wer e reported. Conclusion: Mild to moderate liver impairment has no clini cally relevant effect on candesartan pharmacokinetics, and no dose adj ustment is required for such patients.