The influence of first pass metabolism on the development and validation of an IVIVC for metoprolol extended release tablets.

To investigate the influence of alpha-hydroxymetoprolol (AHM) and 4-(2-hydroxy-3-isopropylaminopropoxy)-phenylacetic acid (ACMB), both derived from its first pass metabolism of metoprolol, an in vitro in vivo correlation incorporating first pass metabolite data for metoprolol extended release formulations was developed. Three different releasing formulations (slow (S), moderate (M) and fast (F), 100 mg) of metoprolol were evaluated in a previously reported clinical study. The non-first pass effect (Non-FPE) in vitro in vivo correlation (IVIVC) was developed using a fraction of metoprolol dissolved and a fraction of total drug (metoprolol + metabolites) as the absorption data for various combinations of formulations (S/M/F, M/F, S/M, and S/F).

Development and validation of a non-linear IVIVC model for a diltiazem extended release formulation.

To develop and validate internally an in vitro-in vivo correlation (IVIVC) for a diltiazem multi-particulate bead extended release formulation. In vitro dissolution of diltiazem capsules was examined using the following methods: USP Apparatus II (paddle) at 100 rpm and USP Apparatus III at 30 dpm. Seven healthy subjects received three diltiazem formulations (90 mg): slow (S), moderate (M), fast (F) releasing and an oral solution (90 mg).