Relationships between acute and chronic beta-blocking effects of bisoprolol in healthy volunteers: a practical approach to predict intensity of beta-blockade.
Bisoprolol is a selective beta 1-adrenoceptor antagonist devoid of partial agonist activity that can be used for treatment of chronic and acute myocardial ischemia. In this condition, it is important to demonstrate that a stable beta-blocking effect at steady state can be predicted by a mathematical model determined by plasma concentration-effect relationship after an acute intravenous (i.v.) dose. This relation was studied in 10 healthy volunteers in a double-blind, randomized, cross-over, placebo-controlled study after a 5-min i.v. infusion of bisoprolol (5 mg) or placebo. Standardized exercise tests were recorded at different times for 48 h after infusion with simultaneous bisoprolol assay (high-performance liquid chromatography, HPLC) in plasma. After a 1-week interval, subjects received oral bisoprolol (10 mg once daily) for 5 days and exercise tests were repeated on day 5 before and 2, 3, and 4 h after dosing, with bisoprolol plasma level determined simultaneously. In the acute period, bisoprolol significantly decreased exercise heart rate (HR: peak effect -20.5 +/- 4%) as compared with placebo. There was a direct relationship (no hysteresis) between beta-blockade and plasma concentrations with a sigmoid (7 subjects) or a linear (3 subjects) best-fit model. After repeated bisoprolol administration, steady-state plasma levels were achieved and 88% of the observed decreases in exercise HR were within the 95% confidence interval (CI) for individual prediction. These data suggest that bisoprolol-induced beta-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.
Jamin
P
P
Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, France.
LeCoz
F
F
Funck-Brentano
C
C
Poirier
J M
JM
Jaillon
P
P
D000328:Adult; D017298:Bisoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004311:Double-Blind Method; D005080:Exercise Test; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008954:Models, Biological
D017298:Bisoprolol