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 indapamide was compared to a 1.5 mg sustained release (SR) formulation of indapamide 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 second 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 dosing interval (24 h). Following a single oral administration the SR formulation 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 and 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 characteristics as compared to the IR formulation. Food co-administration had no effect on dose-normalised AUC for the SR formulation. After repeated administration, 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 lower compared to the IR formulation. After dose correction there was no change in AUC(r) (726 +/- 207 and 690 +/- 183 ng.mL(-1).h for SR and IR, respectively). The elimination parameters (t(1/2z), Ae(r) and CLr) remained unchanged. The SR formulation showed sustained release of indapamide with a reduction 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.