A comparative bioequivalence study of two prolonged-release metoprolol preparations

Introduction. Extended release metoprolol formulations display a reduced rate of absorption and a more uniform release characterized by lower peaks, longer time to peak and smaller peak to trough variation, and this allows for convenient once daily administration. A major advantage of extended release metoprolol formulations lies in the higher cardio-selectivity of lower rather than higher metoprolol plasma concentrations. In addition, the lower peak plasma concentrations tend to reduce adverse effects and, therefore, improve patient compliance. Bioavailability of a generic (Beto ZK, Sandoz GmbH) and a brand name (Betaloc ZOK, AstraZeneca AB) extended-release metoprolol preparation was investigated using both in vitro and in vivo studies to determine if these two formulations were bioequivalent and, thus, safe and interchangeable. Material and methods. Release profiles: Dissolution tests measuring the release of active substance from prolonged-release metoprolol preparations were carried out according to the European Pharmacopoeia (Ph. Eur.) specifications using a release apparatus with paddle mixer (apparatus 2), in a phosphate buffer at pH 6.8. Single dose bioequivalence study : An open, random- ized, 2-way crossoverstudy comparing metoprolol succinate 47.5 mg from modified-release tablets between the Sandoz and AstraZeneca formulations was conducted in healthy volunteers under fasting conditions. Steady state bioequivalence study: A multiple dose study was conducted to compare the steady state pharmacokinetics between the Sandoz and AstraZeneca formulations. This study was an open, randomized, 2 periods, 2-way crossover study between Sandoz metoprolol succinate 190 mg modified-release tablets and AstraZeneca 190 mg modified-release tablets administered as multiple oral doses under fasting conditions in healthy volunteers. Results. In vitro dis- solution tests, using identical methods to those described by Sieradzki et al. (1), showed similar dissolution profiles between Betaloc ZOK (AstraZeneca) and Beto ZK (Sandoz) according to the f2 similarity factor test. Furthermore, in vivo single dose and steady state clinical studies demonstrated bioequivalence between the two formulations as judged by AUC, Cmax and tmax. Finally, none of the AstraZeneca batches tested in this study were capable of yielding a complete release profile at 20 h as reported by Sieradzki et al. (1). Conclusions. The cumulative in vitro and in vivo results reported in this investigation show that the Sandoz and AstraZeneca formulations are bioequivalent, and the contradicting results reported by Sieradzki et al. (1) can best be explained by the use of an AstraZeneca batch that may have been on the borderline of specifications . Geriatria 2012; 6: 34-40.