title: Comparative pharmacokinetics and pharmacodynamics of two marketed bid formulations of diltiazem in healthy volunteers.
abstract: Cardizem SR and Bi-Tildiem were both approved in their respective countries on the basis of clinical trials demonstrating efficacy and safety in the treatment of angina pectoris. In this cross-over randomized study, we assessed whether these two sustained-release formulations of diltiazem have equivalent pharmacokinetic and pharmacodynamic profiles. Twenty-four young healthy male volunteers were hooked to Holters and ambulatory blood pressure monitors for 24 h to establish baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), sinus rate and PR intervals. They then received a single dose of 120 mg of diltiazem from one formulation. The pharmacodynamic measurements were recorded for a further 24 h and blood samples were collected over 36 h for evaluation of diltiazem in plasma by a high-performance liquid chromatogrpahic (HPLC) method. The procedures were repeated with the alternate formulation after a 7 d wash-out. Pharmacokinetics showed statistically significant (p < 0.01) differences in AUC0-12 with means (+/- SD) of 519.2(+/- 172.8) and 429.6(+/- 147.2) ng h ml-1, AUC0-36 of 835.6(+/- 281.6) and 730.9 (+/- 271.5) ng h ml-1 and Cmax of 89.1(+/- 30.3) and 61.1(+/- 21.2) ng ml-1 for Cardizem SR and Bi-Tildiem, respectively. The only pharmacodynamic parameter showing a statistically significant difference in change from baseline between the two formulations was DBP with mean (+/- SD) change in AUC0-12 of -13.6(+/- 20.8) and +8.4(+/- 31.7) mm Hg h (p = 0.0135) and in AUC0-24 of -33.0(+/- 43.7) and -0.3(+/- 59.2) mm Hg h (p = 0.0463) for Cardizem SR and Bi-Tildiem, respectively. These findings suggest that assessment of efficacy of sustained-release formulations of diltiazem by bioequivalence could be misleading. They also confirm that a single dose of diltiazem does not elicit a significant pharmacodynamic response in healthy volunteers. Equivalence for such formulations should therefore be demonstrated by pharmacodynamic evaluation or clinical studies in a patient population.
authors.affiliation: Department of Pharmacology, Université de Montréal, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Guimont
authors.forename: H
authors.initials: H
authors.lastname: Landriault
authors.forename: K
authors.initials: K
authors.lastname: Klischer
authors.forename: M
authors.initials: M
authors.lastname: Grace
authors.forename: C
authors.initials: C
authors.lastname: Lambert
authors.forename: G
authors.initials: G
authors.lastname: Caillé
authors.forename: D
authors.initials: D
authors.lastname: Gossard
authors.forename: A
authors.initials: A
authors.lastname: Russell
authors.forename: M
authors.initials: M
authors.lastname: Raymond
authors.forename: E
authors.initials: E
authors.lastname: Hutchings
mesh_terms: D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004110:Diltiazem / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006801:Humans; D008297:Male; D013810:Therapeutic Equivalency
chemical_list: D003692:Delayed-Action Preparations; D004110:Diltiazem