Comparison of oral and oral sustained-release rilmenidine in healthy volunteers and correlation with in vitro sustained-release properties

Background: Rilmenidine is a centrally-acting antihypertensive. At present, the dosage for rilmenidine is ling once a day, which in some patients need s 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 develope d at a dose of 2mg. Objective: To investigate the relationship between in vitro and in vivo cha racteristics of dissolution of the SR formulation, and to compare the clini cal effects and pharmacokinetics of this formulation of rilmenidine in heal thy volunteers with those of a solution. Design: Double-dummy, double-blind, randomised, two-way, single-dose crosso ver study with a 6-day washout between administrations. Participants: Four healthy male and four healthy female volunteers, aged IS to 27 years. Methods: Rilmenidine was administered either as a I mg solution or as a 2mg SR tablet. Blood samples were taken prior to drug administration and at va rious times up to 36 hours after administration, and plasma was analysed fo r unchanged rilmenidine. Deconvolution was used to determine the in vivo di ssolution of the tablet, which was compared with the in vitro dissolution u sing linear regression. In order to estimate the prediction error of this c orrelation, the observed in vivo results were compared with the predicted i n vivo kinetics according to the appropriate US Food and Drug Administratio n (FDA) guideline. The clinical effects were evaluated by blood pressure an d 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 co ncentration-time curve (AUC) and maximum observed concentration (C-max,) de viated 6.7% and 12% from the observed values. The mean absolute average int ernal prediction errors of the in vitro-in vivo correlation were 32% for AU C and 14% for Cmax. Cmax values were 3.7 +/- 0.77 mug/L with the solution a nd 2.6 +/- 0.32 mug/L after the tablet, normalised to a 1mg dose. These con centrations 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 con centration was greater than 75% of C-max (t(75)) was 3.4h longer for the ta blet than for the solution (95% confidence interval 0.5, 6.3h). The relativ e 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 m aximum 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 viv o correlation exceeded FDA guideline values, the in vitro dissolution kinet ics of the SR tablets are predictive of the in vivo dissolution kinetics. H owever, the pharmaco-kinetic properties of rilmenidine appear to be highly variable, as illustrated by the high variability in relative bioavailabilit y. The clinical effects of the rilmenidine 2mg SR tablet and the ling solut ion were not statistically significantly different.