Abbildung 4: CIBIS II - Cardiac Insufficiency Bisoprolol Study - Design
Receptor occupancy detected by an in vitro incubation of plasma samples with a ß-adrenoceptor preparation allows for a prediction of the relative extent of ß-adrenoceptor antagonistic effects in man. In this study the time course of plasma concentration after a single oral dose of 100 mg of bisoprolol - a dosage far beyond the therapeutic dose range - was compared with the ß-adrenoceptor occupancy of the two adrenoceptor subtypes in an ex-vivo/in-vitro assay. 24 hours after the administration of 100 mg bisoprolol, there was no longer any ß2-adrenoceptor occupancy detected in the plasma samples. Up to that time, plasma levels far exceeded the normal therapeutic range. Therefore an occupancy of the ß2-receptors is practically not to be expected under therapeutic conditions. 36 to 60 hours after a single oral dose of 100 mg of bisoprolol, plasma concentrations similar to a steady state condition after once daily dosage of 10 mg were found. At an 80 % occupancy of ß1-receptors, there was no occupancy of ß2-receptors seen with bisoprolol, whilst under 200 mg of atenolol (slide 4) when there was a maximum occupancy of ß1-receptors of 80%, 25% of ß2-receptors were occupied as well. Occupancy of the ß1-receptors with bisoprolol is in the range of approximately 80-30 % for the therapeutic dose range of 5-10 mg.