Toprol XL - Clinical Pharmacology

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The trial was terminated early for a statistically significant reduction in all-cause mortality (34%, nominal p= 0.00009). The risk of all-cause mortality plus all-cause hospitalization was reduced by 19% (p= 0.00012). The trial also showed improvements in heart failure-related mortality and heart failure-related hospitalizations, and NYHA functional class. The table below shows the principal results for the overall study population. The figure below illustrates principal results for a wide variety of subgroup comparisons, including US vs. non-US populations (the latter of which was not pre-specified).

The combined endpoints of all-cause mortality plus all-cause hospitalization and of mortality plus heart failure hospitalization showed consistent effects in the overall study population and the subgroups, including women and the US population.

However, in the US subgroup (n= 1071) and women (n= 898), overall mortality and cardiovascular mortality appeared less affected. Analyses of female and US patients were carried out because they each represented about 25% of the overall population. Nonetheless, subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.

Clinical Endpoints in the MERIT-HF Study

Risk

Number of Patients Relative Reduction

Placebo TOPROL-XL Risk with Nominal

Clinical Endpoint n= 2001 n= 1990 (95% CI) TOPROL-XL P-value

All-cause mortality 767 641 0.81 19% 0.00012 plus all-cause (0.73-0.90)

hospitalization *

All-cause mortality 217 145 0.66 34% 0.00009 (0.53-0.81)

All-cause mortality 439 311 0.69 31% 0.0000008 plus heart failure (0.60-0.80)

hospitalization *

Cardiovascular 203 128 0.62 38% 0.000022 mortality (0.50-0.78)

Sudden death 132 79 0.59 41% 0.0002 (0.45-0.78)

Death due to 58 30 0.51 49% 0.0023 worsening (0.33-0.79)

heart failure

Hospitalizations 451 317 N/ A N/ A 0.0000076 due to worsening

heart failure *

Cardiovascular 773 649 N/ A N/ A 0.00028 hospitalization *

* Time to first event

* Comparison of treatment groups examines the number of hospitalizations

(Wilcoxon test); relative risk and risk reduction are not applicable.

Results for Subgroups in MERIT-HF

Pharmacokinetics

In man, absorption of metoprolol is rapid and complete. Plasma levels following oral administration of conventional metoprolol tablets, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism.

Metoprolol crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration.

Plasma levels achieved are highly variable after oral administration. Only a small frac-tion of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R-and S-enantiomers, and is primarily metabolized by CYP2D6. When administered orally, it exhibits stereoselective metabolism that is dependent on oxidation phenotype. Elimination is mainly by biotransformation in the liver, and the plasma half-life ranges from approximately 3 to 7 hours. Less than 5% of an oral dose of metoprolol is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no beta-blocking activity.

Following intravenous administration of metoprolol, the urinary recovery of unchanged drug is approximately 10%. The systemic availability and half-life of metoprolol in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure.

Metoprolol is metabolized predominantly by CYP2D6, an enzyme that is absent in about 8% of Caucasians (poor metabolizers) and about 2% of most other populations.

CYP2D6 can be inhibited by a number of drugs. Concomitant use of inhibiting drugs in poor metabolizers will increase blood levels of metoprolol several-fold, decreasing metoprolol's cardioselectivity. (See PRECAUTIONS, Drug Interactions.) In comparison to conventional metoprolol, the plasma metoprolol levels following administration of TOPROL-XL are characterized by lower peaks, longer time to peak and significantly lower peak to trough variation.

The peak plasma levels following once-daily administration of TOPROL-XL average one-fourth to one-half the peak plasma levels obtained following a corresponding dose of conventional metoprolol, adminis-tered once daily or in divided doses. At steady state the average bioavailability of metoprolol following administration of TOPROL-XL, across the dosage range of 50 to 400 mg once daily, was 77% relative to the corresponding single or divided doses of conventional metoprolol. Nevertheless, over the 24-hour dosing interval, ß 1 -blockade is comparable and dose-related (see CLINICAL PHARMACOLOGY). The bioavailability of metoprolol shows a dose-related, although not directly proportional, increase with dose and is not significantly affected by food following TOPROL-XL administration.