PHARMACOKINETICS OF THE CONTROLLED-RELEASE NISOLDIPINE COAT-CORE TABLET FORMULATION

The pharmacokinetics, safety, and tolerability of the novel once-daily ''coat-core'' formulation of the calcium antagonist nisoldipine were investigated in 4 randomized nonblind studies A - D in 52 healthy volu nteers, immediate-release or intravenous formulations were administere d as reference in 3 studies, The objective of the present studies was to select the optimum controlled-release formulation (A), compare it t o the immediate-release tablet at steady-state (B), determine the abso lute bioavailability (C), and investigate bioequivalence after a small change in composition (D), Comparative pharmacokinetic properties: Me an residence time and apparent terminal half-life of nisoldipine in th e coat-core formulation were significantly increased in comparison to administration via the intravenous route or the oral immediate-release formulation. Concentration profiles could be described with a 3-segme nt input model, Steady-state conditions were established with the seco nd dose of nisoldipine coat-core and accumulation from first dose to s teady-state accounted for 46% as expected due to the contribution of A UC beyond 24 h. At steady-state the coat-core formulation produced a p lateau-shaped profile of nisoldipine plasma concentrations throughout the 24 h dosing interval and the peak-trough fluctuation was reduced b y approximately 4fold, compared to the immediate-release tablet in a b .i.d, regimen. While the absolute bioavailability of the drug in the c oat-core tablet was 5.5%, its relative bioavailability was greater by 1.5-fold compared to the immediate-release tablet. This can be attribu ted to release of drug in the colon where the contribution of the gut wall to presystemic metabolism is reduced resulting in an increase in bioavailability as compared to stomach and small intestine. The inters ubject variability of nisoldipine coat-core pharmacokinetics was compa rable to that of the immediate-release tablet, The within-subject (int raindividual) variability was considerably smaller. Based on its pharm acokinetic profile the side chain-hydroxylated metabolite M 9 is not e xpected to contribute significantly to the antihypertensive effect of nisoldipine coat-core, In vitrolin vivo correlation: There was a rank order correlation between in vitro release rate of 3 different nisoldi pine coat-core formulations and their noncompartmental pharmacokinetic parameters, a decrease in dissolution rate leading to increased bioav ailability in vivo. Likewise, the mean dissolution times in vitro and in vivo were correlated in rank order. A linear (level A) correlation could be established within approximately 0 - 6 hours (in vitro) corre sponding to 0 - 12 hours in vivo. The change in slope of the correlati on curve after approximately 12 hours (in vivo) most likely reflects c hanges in both rate and extent of nisoldipine absorption in different sections of the gastrointestinal tract. Safety: In the present studies the drug was safe and well tolerated, adverse events related to perip heral vasodilatation being less frequent with the coat-core tablet com pared to intravenous or immediate-release formulations.