N. Frey (1), M. Dubard (1), J.M.A. Van Gerven (2), and R. Jochemsen (1)
1) I.R.I.S. Courbeyoie, France. 2) CHDR Leiden, The Netherlands
Rilmenidine is a centrally-acting antihypertensive drug with binding selectivity to newly described I, imidazoline receptors over G2-adrenoceptors. The drug is used in the treatment of essential hypertension at the oral dose of 1 mg once or twice a day. Clinical experience indicates that, at 1 mg per day, blood pressure control might not be maintained for 24 h per day in all patients.
A way to approach this problem is to develop a sustained release formulation which will maintain plasma levels in an effective concentration range over 24 hours after administration. To assist in the determination of the optimum concentration-time profile, a clinical pharmacology study was designed to establish the concentration-clinical effect relationship. Twenty-seven mild to moderate hypertensive patients were included in a placebo-controlled, partial cross-over, double-blind study. Patients consecutively received two of three 12-hour infusion regimens: placebo, 1.45 mg and 3.3 mg of rilmenidine.
The PK and PK/PD analyses were performed using the non-linear mixed effects model (NONMEM) program. In order to build a population PK model with a larger number of individuals, blood samples drawn after intravenous infusion from a preliminary study in healthy volunteers were pooled with those from the present study.
The PK profiles were fitted by a two-compartment open model with zero-order input. Significant linear relationships were obtained between the total clearance and creatinine clearance and between the total volume of distribution and weight.
The diastolic blood pressure (DBP) was selected for the population PK/PD analysis. A direct negative linear relationship was found between plasma concentrations and the antihypertensive activity of rilmenidine. Therefore, whatever the formulation, the time- course of DBP will inversely follow the PK profile.
Reference: PAGE 7 (1998) Abstr 685 [www.page-meeting.org/?abstract=685]
Poster: poster