Frey, N., Laveille, C., Kiefer, Ph., Laudignon, N. And Jochemsen, R.
I.R.I.S. Courbevoie, France.
Gliclazide is a sulphonylurea which possesses hypoglycaemic activity and acts against both platelet adhesiveness and aggregation. Owing to its double action (metabolic and vascular), it has found extensive world-wide clinical use for the treatment of type 2 diabetes.
A new formulation of gliclazide (S-5702) has been developed in order to get a pharmacokinetic profile allowing a single daily administration.
Two phase I studies were performed to determine the S-5702 pharmacokinetics after single administration. Sustained release properties were confirmed with a maximum plasma concentration which peaked at approximately 6h after ingestion and with a large t75 about 6h. Cmax and AUC were proportional to the dose.
To determine the minimal efficient dose of this new formulation of gliclazide, a parallel phase II study has been carried out with 224 type 2 diabetics. Patients were treated orally once a day for eight weeks with placebo or one of the following doses of S-5702: 15, 30, 60, 90 and 135 mg. Sparse blood samples were collected after eight weeks of treatment, just before the last administration and at 2h and 6h or 8h after the last administration. In order to investigate the relationship between drug effect and the gliclazide pharmacokinetics, fasting plasma glucose (FPG) levels were determined after the wash-out period, and then after 1, 4 and 8 weeks of treatment.
PK data from the two phase I and the phase II studies were pooled and then analysed with mixed effect modelling in the computer program NONMEM.
A one-compartment open model with zero-order input described adequately S-5702 pharmacokinetics. The analyses of covariate effects showed a significant correlation between clearance and age.
A population PK/PD analysis is in progress in order to investigate the relationship between the variation of FPG response and the time to steady state effect, the initial value of FPG and the drug exposition like dose, AUC or concentration at steady state.
Results of this study will be presented in June 1997 at Glasgow.
Reference: PAGE 6 (1997) Abstr 656 [www.page-meeting.org/?abstract=656]
Poster: poster