Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy volunteers

The bioavailability patterns of a 100 mg metoprolol controlled release tablet and a 10 mg bisoprolol normal release tablet were compared in a single dose crossover study in 12 healthy subjects. The plasma drug concentration levels were measured for 36 h post-dose, using HPLC with fluorimetric detection. The 2 formulations were equally well tolerated, headache being the most frequently reported adverse event. Episodes of bradycardia (heart rate < 50 bpm) occurred at a similar rate with both formulations. The plasma metoprolol profile differed significantly (p < 0.05) from the bisoprolol profile regarding time to maximum concentration, mean residence time, the ratio of peak concentration (C-max) to the area under the curve (AUG) and the plateau time as estimated from the half-value duration. The average drug plasma concentration observed 24 h after administration still accounted for 54% of the C-max value for the metoprolol controlled release tablet, but only 23% with the bisoprolol normal release tablet. A large inter-individual variability was seen in the bioavailability of metoprolol, with 3 subjects (characterised as CYP2D6 deficient) exhibiting AUC values 8 - 10 times larger than in the other subjects. The controlled release pattern of the formulation was similar in slow and fast metabolizers. No such variability pattern was apparent for bisoprolol. The findings allow to conclude that, after administration of the metoprolol controlled release tablet, the rate of absorption of the active principle is significantly slower, therefore yielding more constant plasma concentration levels over the 24 h post-dose period, than after administration of the bisoprolol normal release tablet.