THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION - MORNING AGAINST BEDTIME

Twenty-three young, healthy, male volunteers received, in a randomized crossover design, 240 mg of a once-a-day diltiazem formulation at 08: 00 (AM) or 22:00 (HS) for 6 days. A 7 day washout period was observed between the two modes of administration. Diltiazem plasma concentratio ns were monitored every hour for 24 h and at 30, 36, and 48 h after th e last dose. Differences were found between AM and HS dosing for C-min (mean (SD)=47.2 (25.8) against 39.6 (21.1) ng mL(-1), p=0.038), AUC(0 -24) (2008 (814) against 1754 (714) ng h mL-1, p=0.024), and AUC(0-48) (2662 (1244) against 2395 (238) ng h mL(-1), p=0.034). Overall the tw o modes of administration did not produce bioequivalent pharmacokineti c profiles. Also HS dosing gave significantly higher plasma concentrat ions of diltiazem in the early morning hours when the incidence of car diovascular events is higher. If one assumes a strong correlation betw een plasma concentrations and myocardial protection then I-IS dosing s hould be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advan tage.