Pharmacokinetic and Pharmacodynamic Comparison of Metoprolol CR/ZOK Once Daily with Conventional Tablets Once Daily and in Divided Doses
Authors: Lücker Peter , Moore George , Wieselgren Ingrid , Olofsson Bertil , Bergstrand Robert 
Published: March 2013

Four studies of identical design, each on 18 young healthy subjects, were undertaken to study the pharmacokinetics and beta1‐receptor blockade at steady state after a once daily dose (od) of 100, 200, 300 and 400 mg of metoprolol CR/ZOK (a new controlled release preparation) in comparison with 100 mg dosages (od, bid, tid and qid, respectively) of conventional metoprolol tablets (CT). All studies were of randomized three‐way crossover design with 7‐day double‐blind treatment periods separated by 7‐day single‐blind washout periods. A number of predose plasma concentrations and assessments of beta1‐blockade were made during the study and a full pharmacokinetic and pharmacodynamic study was performed on day 7.

The maximal plasma concentration, Cmax, was significantly lower after metoprolol CR/ZOK compared to CT after all doses—the most pronounced difference being observed after the 100 mg dose when both preparations were given once daily (145 nmol/L vs 606 nmol/L) and the least difference after the 400 mg dose when metoprolol CT was given every 6 hours (837 nmol/L vs 1111 nmol/L). The maximal plasma concentration occurred later after metoprolol CR/ZOK than CT in all studies (median 2.5–4.1 hours vs 1.0–1.2 hours). The trough plasma concentration, Cmin, was significantly higher after 100 mg metoprolol CR/ZOK compared to CT dosed once daily; Cmins were comparable between the two preparations in the 200 mg and 300 mg studies and lower after metoprolol CR/ZOK in the 400 mg study (278 nmol/L vs 469 nmol/L). In all four studies the AUCs were significantly lower after metoprolol CR/ZOK compared to CT with the mean relative bioavailability being approximately similar (73–84%).

All metoprolol treatments produced a statistically significant beta1‐blockade (measured as percent reduction of exercise induced tachycardia) throughout the whole day compared to placebo except in the 100 mg study where the effect of once daily CT did not differ from placebo during the last 6 hours. Consequently, a significantly higher beta1‐blockade was observed after metoprolol CR/ZOK compared to CT in this latter period. The maximum beta1‐blockade (Emax) after CR/ZOK 100 mg was significantly lower than after CT 100 mg once daily (12.6% vs 23.3%) but when CT was given in divided doses from 200 to 400 mg daily, Emax did not differ between the two formulations. Once daily administration of 100 mg of both products resulted in a significantly higher beta1‐blockade 24 hours after dosing with CR/ZOK compared to CT, but when CT was taken in divided doses this difference between the treatments was less pronounced.

There were no significant differences in overall extent of beta1‐blockade (AUEC, area under the effect curve) between the two products in any study. The 90% confidence limits for the difference in AUEC between products expressed as percentage of the mean AUEC for metoprolol CT in the 200, 300 and 400 mg studies were narrow (91–114%, 86–120%, 92–103%) indicating bioequivalent effects. The 90% confidence limits in the 100 mg study, however, were wide (80–158%) and nonconclusive for equivalence.