Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers.

OBJECTIVE

The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation.

METHODS

Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects.

RESULTS

Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding Cmax of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination.

CONCLUSION

The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination.