Pharmacokinetics of sustained and immediate release formulations of indapamide after single and repeated oral administration in healthy volunteers

The pharmacokinetics of a 2.5 mg immediate release (IR) formulation of inda pamide was compared to a 1.5 mg sustained release (SR) formulation of indap amide after single and repeated oral administration dose using double blind randomised cross-over studies. In the first study, 12 subjects received a single dose of each treatment: IR fasted, SR fasted or with food. In the se cond study one tablet of either formulation was administered daily for one week at breakfast. In each study, blood samples were collected pre dose (C- min) and up to 120 h after the last dose. Urine was collected over the dosi ng interval (24 h). Following a single oral administration the SR formulati on had a lower dose-normalised C-max compared to the IR formulation (17.6 /- 6.3 vs. 39.3 +/- 11.0 ng.mL(-1), respectively), a much longer t(max) (12 .3 +/- 0.4 vs. 0.8 +/- 0.3 h) and a greater t(75) (15.3 +/- 6.1 vs. 1.8 +/- 1.4 h) but there were no differences in dose-normalised AUC (559 +/- 125 a nd 564 +/- 146 ng.h.mL(-1)) nor in t(1/2z) values (14.8 +/- 2.8 vs. 18.4 +/ - 13.4 h). The SR formulation clearly demonstrated sustained release charac teristics as compared to the IR formulation. Food co-administration had no effect on dose-normalised AUC for the SR formulation. After repeated admini stration, steady-state was achieved by day 5. The absorption rate of the SR formulation was lower and the 24 h peak-to-trough fluctuation was 4-fold l ower compared to the IR formulation. After dose correction there was no cha nge in AUC(r) (726 +/- 207 and 690 +/- 183 ng.mL(-1).h for SR and IR, respe ctively). The elimination parameters (t(1/2z), Ae(r) and CLr) remained unch anged. The SR formulation showed sustained release of indapamide with a red uction in peak concentration, while steady-state level was not affected by formulations. The two formulations have the same bioavailability. (C) 2000 Editions scientifiques et medicales Elsevier SAS.