C. Laveille, M. Chic, F. Dubois, R. Jochemsen
Institut de Recherches Internationales Servier, 6 place des Pleïades 92415 Courbevoie Cedex.
Indapamide is a very effective and safe sulphonamide diuretic, on the market at the dose of 2.5mg, for the treatment of patients with mild to moderate hypertension. Indapamide has high affinity for carbonic anhydrase present in large quantities in the erythrocytes and blood concentrations are 3 times higher than plasma concentrations. Two new projects are actually under development for this compound, one with a new sustained release form to allow administration at lower dose (1.5mg), without reduction in antihypertensive activity over a 24 hour period, and the other one an association with an ACE inhibitor (Perindopril 4mg) to increase efficacy and improve the percentage of normalized patients.
Due to the sensitivity problem to analyze Indapamide in plasma after administration of 1.5mg, all Indapamide analyses for the sustained release project were performed in blood. .On the contrary, for the association project, for practical reasons, plasma samples were analyzed because Perindoprilate is analyzed in plasma. For these reasons two population pharmacokinetic models (using respectively plasma data and blood data) were derived from phase I data for estimating Indapamide pharmacokinetic parameters utilizing the NONMEM computer program.
The first one used, after repeated administration of I.R Indapamide (2.5mg), 501 plasma concentrations from 36 subjects and was developed to study the influence of coadministration of Perindopril (4mg). After validation of the final model, a bayesian estimation of the pharmacokinetic parameters will be performed during phase III studies with sparse data. Furthermore phase III studies with old patients and renal failure patients will be performed with the association and used to add a stage in model building.
The second one used,, after repeated administration of I.R Indapamide (2.5mg) and S.R Indapamide (1.5mg), 483 blood concentrations from 42 patients and was developed to study both the influence of the galenic form and the influence of the renal function on Indapamide pharmacokinetics (studied with the S.R form).
Reference: PAGE 2 () Abstr 909 [www.page-meeting.org/?abstract=909]
Poster: oral presentation