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 volunteers. Immediate-release or intravenous formulations were administered as reference in 3 studies. The objective of the present studies was to select the optimum controlled-release formulation (A), compare it to the immediate-release tablet at steady-state (B), determine the absolute bioavailability (C), and investigate bioequivalence after a small change in composition (D). Comparative pharmacokinetic properties: Mean residence time and apparent terminal half-life of nisoldipine in the 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-segment input model. Steady-state conditions were established with the second dose of nisoldipine coat-core and accumulation from first dose to steady-state accounted for 46% as expected due to the contribution of AUC beyond 24 h. At steady-state the coat-core formulation produced a plateau-shaped profile of nisoldipine plasma concentrations throughout the 24 h dosing interval and the peak-trough fluctuation was reduced by approximately 4-fold, compared to the immediate-release tablet in a b.i.d. regimen. While the absolute bioavailability of the drug in the coat-core tablet was 5.5%, its relative bioavailability was greater by 1.5-fold compared to the immediate-release tablet. This can be attributed 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 intersubject variability of nisoldipine coat-core pharmacokinetics was comparable to that of the immediate-release tablet. The within-subject (intraindividual) variability was considerably smaller. Based on its pharmacokinetic profile the side chain-hydroxylated metabolite M 9 is not expected to contribute significantly to the antihypertensive effect of nisoldipine coat-core. In vitro/in vivo correlation: There was a rank order correlation between in vitro release rate of 3 different nisoldipine coat-core formulations and their noncompartmental pharmacokinetic parameters, a decrease in dissolution rate leading to increased bioavailability 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) corresponding to 0-12 hours in vivo. The change in slope of the correlation curve after approximately 12 hours (in vivo) most likely reflects changes in both rate and extent of nisoldipine absorption in different sections of the gastrointestinal tract. RESULTS In the present studies the drug was safe and well tolerated, adverse events related to peripheral vasodilatation being less frequent with the coat-core tablet compared to intravenous or immediate-release formulations.