European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V

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

PMID 11976018


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). Direct convolution approaches predicting metoprolol concentrations and indirect convolution predicting total drug concentrations (metoprolol + metabolites) were used to determine in vivo behavior. The Non-FPE IVIVC using the S/M/F formulations displayed the strongest relationship (r2 > 0.92). The IVIVC using the indirect approach was predictive of both the C(max) (prediction errors (PE) 4.77, 3.94 and 6.14%) and AUC (10.7, 11.0 and 11.3%) for metoprolol, AHM and ACMB. Poor predictability (PE > 40% for C(max) and AUC) was observed for metoprolol when using the direct methods. The predictability of the IVIVC using the indirect approach as compared to the direct method displays the influence of first pass metabolism on the development and evaluation of an IVIVC for a drug that displays a high extraction ratio. In addition, the indirect IVIVC allows for not only predicting the in vivo performance of the parent drug but also the metabolites formed via the first pass effect.

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α-Hydroxymetoprolol, analytical standard