Pharmaceutical Research

, Volume 10, Issue 1, pp 28–34

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

  • Anders Sandberg
  • Bertil Abrahamsson
  • Agneta Svenheden
  • Bertil Olofsson
  • Robert Bergstrand
Article

DOI: 10.1023/A:1018960626925

Cite this article as:
Sandberg, A., Abrahamsson, B., Svenheden, A. et al. Pharm Res (1993) 10: 28. doi:10.1023/A:1018960626925

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.

extended-release metoprolol steady-state bioavailability day-to-day variability 

Copyright information

© Plenum Publishing Corporation 1993

Authors and Affiliations

  • Anders Sandberg
    • 1
  • Bertil Abrahamsson
    • 1
  • Agneta Svenheden
    • 1
  • Bertil Olofsson
    • 2
  • Robert Bergstrand
    • 3
  1. 1.Department of Biopharmaceutics and Project CoordinationAstra Hässle ABSweden
  2. 2.Department of Medical Statistics and Data ManagementAstra Hässle ABSweden
  3. 3.Department of Clinical PharmacologyAstra Hässle ABSweden