Pharmacokinetic and Pharmacodynamic Comparison of Metoprolol CR/ZOK Once Daily with Conventional Tablets Once Daily and in Divided Doses

Abstract

Four studies of identical design, each on 18 young healthy subjects, were undertaken to study the pharmacokinetics and beta 1-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 beta 1-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 beta 1-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 beta 1-blockade was observed after metoprolol CR/ZOK compared to CT in this latter period. The maximum beta 1-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 beta 1-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.(ABSTRACT TRUNCATED AT 400 WORDS)

A Pharmacokinetic and Pharmacodynamic Comparison of Immediate-Release Metoprolol and Extended-Release Metoprolol CR/XL in Patients with Suspected Acute Myocardial Infarction: A Randomized, Open-Label Study

“…The results from this study, which for the first time compared once daily metoprolol CR/XL 200 mg with multiple dosing of metoprolol IR 50 and 100 mg in patients with acute myocardial infarction, are in agreement with pharmacokinetic results from studies in healthy subjects [16] and in heart failure patients [17]. …”

Effect of Metoprolol Succinate in Patients with Stable Angina and Elevated Heart Rate Receiving Low-Dose β-Blocker Therapy

“…According to one report, atenolol, bisoprolol, and metoprolol were more effective than other β-blockers in managing resting HR in CHD patients 9. Previous studies of multiple patient groups have demonstrated that changes in both 24-h average HR and resting HR were related to the dosage of β-blocker administered 18, 19. In a study involving Chinese CHD patients who were β-blocker-naive, 42.5% and 79.4% of the patients achieved a HR of less than 70 bpm after one and two months of metoprolol succinate treatment, respectively 18.…”

Treatment with β‐blockers—the value of an even plasma concentration over 24 h

“…It has also been shown that metoprolol CR/ZOK produces a more even 1-blockage over 24 h. This is determined by expressing the percentage reduction in exercise heart rate in relation to placebo at intervals throughout the 24 h and comparing the results with those of atenolol and conventional metoprolol tablets (17,20,(22)(23)(24).…”