A Pharmacokinetic and Pharmacodynamic Comparison of Metoprolol CR/ZOK with a Conventional Slow Release Preparation

Abstract

The plasma concentration-time profile and hemodynamic effects of metoprolol after the administration of metoprolol CR/ZOK, a multiple-unit controlled release formulation and a conventional slow release formulation, metoprolol Durules (Astra, AB Hässle, Mölndal, Sweden) once daily, were investigated in 12 healthy men. Data were collected over one 24-hour dose interval at steady state after 5 days of treatment. The study was randomized, three-way, crossover double-blind comparison of metoprolol CR/ZOK 200 mg, metoprolol Durules 200 mg and placebo. The reduction in exercise heart rate compared with placebo treatment was used as a measure of beta 1-blockade. The metoprolol plasma concentration-time profile during treatment with metoprolol CR/ZOK was smooth and uniform, showing a more constant release profile than that obtained with metoprolol Durules. This was demonstrated by the significantly longer time period during which the plasma concentration exceeded 75% of the maximum concentration (T75), for metoprolol CR/ZOK compared with metoprolol Durules (P less than .01). The Fluctuation Index of plasma metoprolol concentration was significantly smaller for metoprolol CR/ZOK than for metoprolol Durules (P less than .001). The pharmacokinetic differences between the formulations also produced differences in the time profiles of exercise heart rate. The percentage fluctuation in exercise heart rate over the dose interval tended to be smaller for metoprolol CR/ZOK. At the start and the end of the dosing interval, the CR/ZOK formulation was significantly more effective (P less than .01). These results indicate that Metoprolol CR/ZOK has a more sustained time profile of beta 1-blockade at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)