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Steady-state Bioavailability and Day-To-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing

Steady-state Bioavailability and Day-To-Day Variability of a Multiple-Unit (CR/ZOK) and a Single-Unit (OROS) Delivery System of Metoprolol After Once-Daily Dosing

A Sandberg, B Abrahamsson, A Svenheden, B Olofsson, R Bergstrand

Pharm Res. 1993 Jan;10(1):28-34.

PMID: 8430057

Abstract:

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8-9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in Cmax and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP119637660	Metoprolol fumarate		119637-66-0	Price

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