The pharmacodynamic and pharmacokinetic profiles of controlled-release formulations of felodipine and metoprolol in free and fixed combinations in elderly hypertensive patients.
OBJECTIVE
The aims of this study were to study the efficacy and tolerability of felodipine extended release (ER) 5 mg and metoprolol controlled release (CR/ZOC) 50 mg given as a fixed combination (Logimax) or as a free combination in elderly (age greater than 60 years) hypertensive patients, using ambulatory blood pressure (BP) monitoring. A secondary aim was to relate the efficacy of the free and fixed combinations with pharmacokinetic profiles.


METHODS
This was a double-blind, placebo-controlled randomised three-way crossover multi-centre study. BP was measured for 26 h using ambulatory blood pressure monitoring (ABPM), which was performed on the last day of the three treatment phases.


RESULTS
Mean sitting BPs, measured during the trough period with ABPM, were significantly lower with both the free and fixed combinations of metoprolol and felodipine than placebo (141/83 mmHg free, 140/83 mmHg fixed, 156/93 mmHg placebo). The mean BPs measured over 24 h using ABPM were 143/82 mmHg, 140/82 mmHg and 158/93 mmHg for the free, fixed and placebo treatment arms, respectively. The trough-to-peak ratios (T:P) were 75% and 79% for the systolic BP and 70% and 70% for the diastolic BP for the free and fixed combinations, respectively. Pharmacokinetic evaluation revealed identical plasma concentration-time curves for felodipine given as the free or fixed combination. Comparison of the plasma concentration-time curves for metoprolol revealed a delay in the release rate from the fixed combination formulation. No significant differences in BP control between the active treatments were noted during this period. Of 26 patients entered into the study, 3 withdrew during active phase for non-drug-related reasons. No patient withdrew from active treatment due to treatment-related adverse events. The frequency of adverse event reporting for the fixed combination of felodipine and metoprolol was similar to that for placebo (60% and 58%, respectively).


CONCLUSIONS
The results suggest that once-daily dosing with either the free or fixed combination of felodipine 5 mg and metoprolol 50 mg produces a significant sustained reduction in systolic and diastolic BP with similar plasma concentration profiles over a 24-h period.
McLay
J S
JS
Department of Medicine and Therapeutics, University of Aberdeen, Polwarth Buildings, Foresterhill, Aberdeen, AB25 2ZD, UK. j.mclay@abdn.ac.uk
MacDonald
T M
TM
Hosie
J
J
Elliott
H L
HL
D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D002940:Circadian Rhythm; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D004311:Double-Blind Method; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D015736:Felodipine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D010919:Placebos
D000959:Antihypertensive Agents; D003692:Delayed-Action Preparations; D004338:Drug Combinations; D010919:Placebos; D008790:Metoprolol; D015736:Felodipine