Abstract
Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in C max and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.
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REFERENCES
J. H. Silas, S. Freestone, M. S. Lennard, and L. E. Ramsay. Comparison of two slow-release formulations of metoprolol with conventional metoprolol and atenolol in hypertensive patients. Br. J. Clin. Pharmacol. 20:387–391 (1985).
A. Sandberg, I. Blomqvist, U. E. Jonsson, and P. Lundborg. Pharmacokinetic and pharmacodynamic properties of a new controlled-release formulation of metoprolol: A comparison with conventional tablets. Eur. J. Clin. Pharmacol. 33:S9–S14 (1988).
P. Lucker, G. Moore, I. Wieselgren, B. Olofsson, and R. Bergstrand. Pharmacokinetic and pharmacodynamic comparison of metoprolol CR/ZOK once daily with conventional tablets once daily and in divided doses. J. Clin. Pharmacol. 30:S17–S27 (1990).
W. Good, L. J. Leeson, S. L. Zak, W. E. Wagner, J. B. Meeker, and J. D. Arnold. Oros controlled-release formulations of metoprolol: An approach to the development of a system for once daily administration. Br. J. Clin. Pharmacol. 19:231S–238S (1985).
N. R. Feliciano, A. A. Bouvet, E. Redalieu, J. Castellana, R. C. Luders, D. J. Schwartz, L. Shum, S. Zak, J. D. Arnold, and P. T. Leese. Pharmacokinetic and pharmacodynamic comparison of an osmotic release oral metoprolol tablet and the metoprolol conventional tablet. Am. Heart J. 120:483–489 (1990).
M. Kendall, S. Akhlaghi, B. Hughes, and H. Lewis. Is metoprolol CR/ZOK more selective than conventional metoprolol and atenolol? J. Clin. Pharmacol. 30:S98–S102 (1990).
C. Tantucci, B. Bruni, M. L. Dottorini, F. Peccini, M. Motolese, J. B. Lecaillon, A. Sorbini, and V. Grassi. Comparative evaluation of cardioselectivity of metoprolol OROS and atenolol: A double-blind, placebo-controlled crossover study. Am. Heart J. 120:467–472 (1990).
A. Sandberg, G. Ragnarsson, U. E. Jonsson, and J. Sjögren. Design of a new multiple-unit controlled-release formulation of metoprolol—metoprolol CR. Eur. J. Clin. Pharmacol. 33:S3–S7 (1988).
F. Theeuwes, D. R. Swanson, G. Guittard, A. Ayer, and S. Khanna. Osmotic delivery systems for the β-adrneoceptor antagonists metoprolol and oxprenolol: Design and evaluation of systems for once-daily administration. Br. J. Clin. Pharmacol. 19:69S–76S (1985).
F. Theeuwes. Elementary osmotic pump. J. Pharm. Sci. 64:1987–1990 (1975).
M. Ervik, K. Kylberg-Hanssen, and L. Johansson. Determination of metoprolol in plasma and urine using high-resolution gas chromatography and electron-capture detection. J. Chromatogr. 381:168–174 (1986).
K. O. Borg, E. Carlsson, K. J. Hoffman, T. E. Jönsson, H. Thorin, and B. Wallin. Metabolism of metoprolol-(3H) in man, the dog and the rat. Acta Pharmacol. Toxicol. 36 (Suppl. V): 125–135 (1975).
K. Balmer, Y. Zhang, P. O. Lagerström, and B. A. Persson. Determination of metoprolol and two major metabolites in plasma and urine by column liquid chromatography and fluorimetric detection. J. Chromatogr. 417:357–365 (1987).
D. Brockmeier. In vitro/In vivo correlation of dissolution using moments of dissolution and transit times. Acta Pharm. Technol. 32:164–174 (1986).
D. Hauschke, V. W. Steinijans, and E. Diletti. A distribution-free procedure for the statistical analysis of bioequivalence studies. Int. J. Clin. Pharmacol. Ther. Toxicol. 28:72–78 (1990).
G. Ragnarsson, A. Sandberg, M. O. Johansson, B. Lindstedt, and J. Sjögren. In vitro release characteristics of a membrane-coated pellet formulation—influence of drug solubility and particle size. Int. J. Pharm. 79:223–232 (1992).
V. A. John. A structured approach to the development of a controlled-release drug delivery system for a β-adrenoceptor blocking drug. J. Contr. Release 11:307–314 (1990).
M. S. Lennard, G. T. Tucker, and H. F. Woods. The polymorphic oxidation of β-adrenoceptor antagonists. Clinical pharmacokinetic considerations. Clin. Pharmacokin. 11:1–17 (1986).
J. C. McGourty, J. H. Silas, M. S. Lennard, G. T. Tucker, and H. F. Woods. Metoprolol metabolism and debrisoquine polymorphism—population and family studies. Br. J. Clin. Pharmacol. 20:555–566 (1985).
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Sandberg, A., Abrahamsson, B., Svenheden, A. et al. Steady-State Bioavailability and Day-to-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing. Pharm Res 10, 28–34 (1993). https://doi.org/10.1023/A:1018960626925
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DOI: https://doi.org/10.1023/A:1018960626925