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Relationships Between Acute and Chronic β-Blocking Effects of Bisoprolol in Healthy Volunteers: A Practical Approach to Predict Intensity of β-Blockade

Summary: Bisoprolol is a selective β1-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 β-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 β-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 β-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.