The Relationship Between Metoprolol Plasma Concentration and Beta1‐Blockade in Healthy Subjects: A Study on Conventional Metoprolol and Metoprolol CR/ZOK Formulations

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Abstract
Four studies using different daily doses (100 mg, 200 mg, 300 mg and 400 mg) have examined the bioequivalence of the once daily formulation metoprolol CR/ZOK and conventional metoprolol tablets (CT). These studies showed metoprolol CR/ZOK to have a similar beta1‐blocking activity to metoprolol CT but that the bioavailability of the new formulation was lower. This paper presents the analysis of data from all four studies, looking at the relationship between plasma concentrations and beta1‐blockade measured as reduction of exercise induced tachycardia.The log linear pharmacodynamic model was used for each of the four doses to compare the two formulations. Mean slopes and intercepts in the linear regression analysis of log plasma concentration of metoprolol versus beta1‐blockade did not differ significantly between CR/ZOK and CT in any of the four studies. After having shown lack of influence of the absorption rate on the plasma concentration—effect relationship, data for CR/ZOK and CT formulations from the 200 mg study were pooled for each individual subject and fitted to an Emaxmodel. The maximal β1‐blocking effect (Emax) was 28% (95% confidence interval: 25–31%) and the plasma concentration for obtaining 50% ofEmax(C50) was 105 nmol/L (95% confidence interval: 74–135 nmol/L). The plasma concentration‐effect data from the 100 mg, 300 mg and 400 mg studies were reasonably well within the 95% prediction interval based on the 200 mg study, which showed the validity of the obtained relationship. The hyperbolic concentration‐beta1‐blocking effect relationship, as described by the Emax‐model explains why a similar or even increased effect is obtained over a dosing interval for metoprolol CR/ZOK compared with metoprolol CT, in spite of the reduced bioavailability of the CR/ZOK formulation.

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