THE INFLUENCE OF TIME OF ADMINISTRATION ON THE PHARMACOKINETICS OF A ONCE-A-DAY DILTIAZEM FORMULATION: MORNING AGAINST BEDTIME |
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Authors: | Jean Thiffault,Hé lè ne Landriault,Denis Gossard,Manon Raymond,Gilles Caillé ,Jean Spé nard |
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Abstract: | 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 concentrations were monitored every hour for 24 h and at 30, 36, and 48 h after the last dose. Differences were found between AM and HS dosing for Cmin (mean (SD)=47·2 (25·8) against 39·6 (21·1) ng mL−1, p=0·038), AUC0–24 (2008 (814) against 1754 (714) ng h mL−1, p=0·024), and AUC0–48 (2662 (1244) against 2395 (238) ng h mL−1, p=0·034). Overall the two modes of administration did not produce bioequivalent pharmacokinetic profiles. Also HS dosing gave significantly higher plasma concentrations of diltiazem in the early morning hours when the incidence of cardiovascular events is higher. If one assumes a strong correlation between plasma concentrations and myocardial protection then HS dosing should be recommended for QD formulation of diltiazem. Clinical studies should be performed to confirm this theoretical pharmacokinetic advantage. |
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Keywords: | diltiazem pharmacokinetics circadian rhythm chronopharmacology |
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