IngentaConnect Comparison of Oral and Oral Sustained-Release Rilmenidine in Heal...

Abstract:

Background: Rilmenidine is a centrally-acting antihypertensive. At present, the dosage for rilmenidine is 1mg once a day, which in some patients needs to be increased to 1mg twice a day. In order to increase the duration of the effect without increasing the occurrence of adverse effects related to peak concentrations, a sustained-release (SR) formulation has been developed at a dose of 2mg.

Objective: To investigate the relationship between in vitro and in vivo characteristics of dissolution of the SR formulation, and to compare the clinical effects and pharmacokinetics of this formulation of rilmenidine in healthy volunteers with those of a solution.

Design: Double-dummy, double-blind, randomised, two-way, single-dose crossover study with a 6-day washout between administrations.

Participants: Four healthy male and four healthy female volunteers, aged 18 to 27 years.

Methods: Rilmenidine was administered either as a 1mg solution or as a 2mg SR tablet. Blood samples were taken prior to drug administration and at various times up to 36 hours after administration, and plasma was analysed for unchanged rilmenidine. Deconvolution was used to determine the in vivo dissolution of the tablet, which was compared with the in vitro dissolution using linear regression. In order to estimate the prediction error of this correlation, the observed in vivo results were compared with the predicted in vivo kinetics according to the appropriate US Food and Drug Administration (FDA) guideline. The clinical effects were evaluated by blood pressure and heart rate measurements and by visual analogue scales (VAS) of alertness, mood and calmness.

Results: The slope of the mean in vitro-in vivo dissolution correlation was 1.1 with a range from 0.71 to 1.7. The average predicted area under the concentration-time curve (AUC) and maximum observed concentration (C) deviated 6.7% and 12% from the observed values. The mean absolute average internal prediction errors of the in vitro-in vivo correlation were 32% for AUC and 14% for C. C values were 3.7 ± 0.77 µg/L with the solution and 2.6 ± 0.32 µg/L after the tablet, normalised to a 1mg dose. These concentrations were reached later for the SR formulation than for the solution (5.4 ± 0.52h compared with 2.1 ± 0.79h). The time during which the concentration was greater than 75% of C (t) was 3.4h longer for the tablet than for the solution (95% confidence interval 0.5, 6.3h). The relative bioavailability of the tablet compared with the solution was 126 ± 54% (coefficient of variation 43%). Both preparations showed similar treatment effects on blood pressure and alertness VAS, with a significantly earlier maximum for the solution (around 3.5h) than for the SR tablet (about 5 to 6h).

Conclusions: Although the internal prediction errors of the in vitro-in vivo correlation exceeded FDA guideline values, the in vitro dissolution kinetics of the SR tablets are predictive of the in vivo dissolution kinetics. However, the pharmacokinetic properties of rilmenidine appear to be highly variable, as illustrated by the high variability in relative bioavailability. The clinical effects of the rilmenidine 2mg SR tablet and the 1mg solution were not statistically significantly different.

Comparison of Oral and Oral Sustained-Release Rilmenidine in Healthy Volunteers and Correlation with In Vitro Sustained-Release Properties