Concentration-effect relationships of two rilmenidine single-dose infusion rates in hypertensive patients.

Objectives: This study was designed to assess the concentration-effect relationships for the antihypertensive effects of rilmenidine in patients to aid in the design of an optimized concentration profile of a sustained-release formulation.

Methods: A placebo-controlled, randomized, double-blind, 2-way partial crossover study was performed in subjects with hypertension. Patients were randomized to receive 2 of 3 possible 12-hour infusion regimens, each consisting of a loading phase (2 hours) and a maintenance phase (10 hours): low-profile infusion (total dose of rilmenidine, 1.45 mg), high-profile infusion (total dose, 3.3 mg), or placebo. Drug plasma concentrations, adverse events, blood pressure, heart rate, and visual analog scales were measured frequently, up to 24 hours after dosing. Salivary flow was determined for up to 15 hours.

Results: The high concentration profile was well tolerated and continued to produce a significant blood pressure reduction of 10.4 mm Hg (systolic)/5.8 mm Hg (diastolic) after 24 hours. The low concentration profile showed no significant effects on blood pressure compared with placebo after 24 hours. Decreases in salivary flow were -36% for the high-profile infusion and -20% for the low-profile infusion compared with placebo. Pharmacokinetic-pharmacodynamic analyses showed infusion rate-independent, linear concentration-dependent reductions in diastolic blood pressure and salivary flow up to the maximum observed rilmenidine concentration for both types of infusion.

Conclusions: The high concentration profile was well tolerated and still produced a significant blood pressure reduction after 24 hours. Pharmacokinetic-pharmacodynamic relationships were linear and unaffected by the rate of infusion. These results should aid in the design of an optimal slow-release profile.