Toprol XL - Clinical Pharmacology

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TOPROL-XL administered once a day, and immediate release metoprolol administered once to four times a day, provided comparable total beta 1 -blockade over 24 hours (area under the beta 1 -blockade versus time curve) in the dose range 100Ð 400 mg. At a dosage of 50 mg once daily, TOPROL-XL produced significantly higher total beta 1 -blockade over 24 hours than immediate release metoprolol. For TOPROL-XL, the percent reduction in exercise heart rate was relatively stable throughout the entire dosage interval and the level of beta 1 -blockade increased with increasing doses from 50 to 300 mg daily. The effects at peak/ trough (ie, at 24-hours post-dosing) were: 14/ 9, 16/ 10, 24/ 14, 27/ 22 and 27/ 20% reduction in exercise heart rate for doses of 50, 100, 200, 300 and 400 mg TOPROL-XL once a day, respectively.

In contrast to TOPROL-XL, immediate release metoprolol given at a dose of 50Ð 100 mg once a day produced a significantly larger peak effect on exercise tachycardia, but the effect was not evident at 24 hours. To match the peak to trough ratio obtained with TOPROL-XL over the dosing range of 200 to 400 mg, a t. i. d. to q. i. d. divided dosing regimen was required for imme-diate release metoprolol. A controlled cross-over study in heart failure patients compared the plasma concentrations and beta 1 -blocking effects of 50 mg immediate release metoprolol administered t. i. d., 100 mg and 200 mg TOPROL-XL once daily. A 50 mg dose of immediate release metoprolol t. i. d. produced a peak plasma level of metoprolol similar to the peak level observed with 200 mg of TOPROL-XL. A 200 mg dose of TOPROL-XL produced a larger effect on suppression of exercise-induced and Holter-monitored heart rate over 24 hours compared to 50 mg t. i. d. of immediate release metoprolol. The relationship between plasma metoprolol levels and reduction in exercise heart rate is independent of the pharmaceutical formulation.

Using the E max model, the maximal beta 1 -blocking effect has been estimated to produce a 30% reduction in exercise heart rate. Beta 1 -blocking effects in the range of 30Ð 80% of the maximal effect (corre-sponding to approximately 8Ð 23% reduction in exercise heart rate) are expected to occur at metoprolol plasma concentrations ranging from 30Ð 540 nmol/ L. The concen-tration-effect curve begins reaching a plateau between 200Ð 300 nmol/ L, and higher plasma levels produce little additional beta 1 -blocking effect. The relative beta 1 -selec-tivity of metoprolol diminishes and blockade of beta 2 -adrenoceptors increases at higher plasma concentrations.