Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (C max ) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC τ ) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Cl O ) decreased by 54%. The terminal half-life (t 1/2 ) of moricizine was not affected, however (2.1 ± 0.5 hours versus 2.4 ± 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the C max of diltiazem significantly (by 36% and increased Cl O by 52%. A small but statistically significant decrease in the t 1/2 from 4.6 ± 1.3 hours to 3.6 ± 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in C max , AUC, or t 1/2 ) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.