Bioequivalence and relative bioavailability of a new diltiazem sustained release formulation

The bioequivalence and relative bioavailability of a new sustained release formulation of diltiazem (120 mg, Diltiazem-Mepha(R) 120 retard, CAS 33286-22-5) in comparison with a 120 mg reference formulation was investigated in a randomised 2-way cross-over study in 18 healthy volunteers following multiple, twice daily dosing for 5 days. Blood samples were taken prior to the morning dose on days 1 to 4 and before and periodically during 32 h after the last administration in the morning of day 5. The diltiazem concentration was determined using a HPLC method. The following primary and secondary pharmacokinetic parameters were derived from the individual plasma concentration time courses on day 5:C-max and AUC(tau) (primary parameters) and PTF, PTS, t(1/2), t(max) and F-rel (secondary parameters). For the new test formulation mean (SD) C-max was 168.9 (49.1) ng/ml and AUC(tau) was 1343 (313) ng . h/ml, whereas these values were 194.7 (44.2) ng/ml and 1460 (444) ng . h/ml for C-max and AUC(tau) of the reference formulation, respectively. Smaller inter-subject variations of the diltiazem plasma concentrations following administration of the test formulation were found, which could be due to an improved retardation principle. However, the point-estimate and 90% confidence interval around the point-estimate fall inside the bioequivalence acceptance range of 0.70-1.43 for C-max and 0.80-1.25 for AU(tau). Therefore, from the results of this study it can be concluded that the test formulation is bioequivalent with the reference formulation following multiple dose, twice daily administration.