Pharmacokinetics of an oral sustained-release diltiazem preparation.

Abstract

The pharmacokinetics of a new oral sustained-release diltiazem preparation (HER-SR, QD) was investigated in dogs and humans. The mean plasma diltiazem concentration in dogs after oral administration of HER-SR showed a prolonged plasma concentration and a double peak. The bioavailability of HER-SR compared with that of a conventional diltiazem preparation (HER) in dogs was approximately 80%, a value that is relatively close to that of humans. The plasma diltiazem concentrations with a double peak in dogs were analyzed using multifraction absorption models. The HER-SR preparation was apparently divided into two fractions (14.3 and 85.7 mg) in the gastrointestinal tract, each fraction was absorbed at rate constants of 4.560 and 0.152 h-1, respectively, and the lag time of the slow-release component was 8.3 h. The plasma diltiazem concentration data in humans after repetitive oral administration of HER-SR were also analyzed using multifraction absorption models. The initial amount of the fast- and slow-release components were 14.8 and 85.2 mg, respectively. The absorption rate constants were 0.730 h-1 for the fast-release component and 0.060 h-1 for the slow-release component. The lag time of absorption for the slow-release component was 6.0 h. The pharmacokinetic parameters were close to those obtained in dogs except for Ka1 and Vd/F. The results confirm that HER-SR had desirable pharmacokinetic characteristics as judged from the simulated plasma diltiazem concentration and the peak-to-trough fluctuation (fluctuation parameters) calculated using the simulated plasma diltiazem concentration. In addition, population pharmacokinetics of HER-SR after repetitive oral administration was examined in humans.