Comparisons of the effects of different long-acting delivery systems on the pharmacokinetics and pharmacodynamics of diltiazem

The benzothiazepine calcium channel antagonist diltiazem is a short-acting drug. To achieve effective 24-h blood pressure control with once-daily dosing, it relies on various extended drug-delivery systems that have grown in importance as a result of the recent reports relating the use of short-acting calcium channel antagonists to increased cardiovascular morbidity. This study examines the pharmacokinetics and resulting pharmacodynamics of two different delivery systems, each loaded with 240 mg of diltiazem and administered to 40 moderately hypertensive patients in a randomized, double-blind crossover trial. After a 4-week, single-blind placebo lead-in, patients with a clinical diastolic blood pressure of ≥100 mm Hg were randomized to either the single or dual microbead diltiazem delivery system for a 4-week period. At the end of this period, each subject was evaluated with 24-h ambulatory blood pressure monitoring and subjected to 24-h inpatient pharmacokinetic analysis on separate days. This was followed by a similar 4-week period in which each subject was treated with the alternative delivery system. For diltiazem, the area under the curve for plasma concentration versus time and the maximum plasma concentration attained by the single microbead system exceeded the values achieved by the dual bead system by 15% and 25%, respectively. These differences were greatest from the 3rd through the 13th h after dosing. During this period, both systolic and diastolic ambulatory blood pressure was significantly lower when the single microbead system was used. When compared with baseline blood pressure, blood pressure reductions achieved with the single microbead system exceeded reductions achieved with the dual microbead system by at least 2 mm Hg for 10 of the 24 postdose hours. Heart rates were slightly reduced but not significantly different. This improved blood pressure control at higher plasma levels of diltiazem suggests that a more efficient delivery system could provide better blood pressure control for identical doses of diltiazem.