Comparison of diltiazem bioavailability from 3 marketed extended-release products for once-daily administration: implications of chronopharmacokinetics and dynamics.
Diltiazem has proven to be an effective antihypertensive and antianginal agent, due to its potent calcium channel blocking activity. The present study was conducted to compare the bioavailability of a new extended release diltiazem HCl capsule formulation (Tiazac) with 2 other currently marketed products (Cardizem CD and Dilacor XR). Fourteen healthy male subjects participated in this randomized, 3-period, multiple daily dose (240 mg for 7 days), crossover bioavailability study. ANOVA and multiple comparison tests showed the parent drug AUC0-tau to be significantly higher after daily dosing with Tiazac than with the other 2 marketed products, but the diltiazem Cmin values were not significantly different between the 3 formulations. Between 5 and 12 hours after drug administration, mean plasma diltiazem levels for Tiazac capsules were found to be significantly higher than those of the 2 other products tested. Comparison of plasma concentrations of metabolites for the 3 capsule formulations by ANOVA and multiple comparison tests showed similar trends as in the case of parent drug concentrations. These findings may be clinically important as higher and more consistent plasma concentrations of diltiazem, and its active metabolite during daytime are needed to counteract higher blood pressures in hypertensive patients due to circadian variations. The new extended release product of diltiazem HCl was found to exhibit significantly differing pharmacokinetics of the parent compound compared to either of the other 2 products tested.
Eradiri
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Research and Development Division, Biovail Corporation International, Mississauga, Ontario, Canada.
Midha
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D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004110:Diltiazem / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D013997:Time Factors
D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D003692:Delayed-Action Preparations; D004110:Diltiazem