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 bi oequivalence is achieved for a new fixed combination of extended-relea se (ER) felodipine and controlled-release (CR/ZOK) metoprolol compared with the free combination of felodipine ER metoprolol CR/ZOK. The sec ond aim was to study whether there was an interaction in pharmacokinet ics and pharmacodynamics between felodipine and metoprolol when admini stered as ER formulation. Methods: Two four-way cross-over studies wer e 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 differe nce 27%) except for a minor deviation regarding C-max 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 treatmen ts. Blood pressure and heart rate was significantly reduced for the fi xed combination compared with felodipine ER in the younger and the eld erly subjects. No significant difference regarding pharmacodynamics wa s detected between the fixed combination and the corresponding free co mbination. Conclusion: The fixed combination consistently provides fai rly constant and effective felodipine and metoprolol concentrations af ter once-daily administration of one tablet. It is clinically intercha ngeable with the free combination of metoprolol CR/ZOK tablets and fel odipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination .