Drug disposition and modelling before and after gastric bypass: immediate and controlled-release metoprolol formulations

AimsThe aim of the present study was to evaluate the disposition of metoprolol after oral administration of an immediate and controlled-release formulation before and after Roux-en-Y gastric bypass (RYGB) surgery in the same individuals and to validate a physiologically based pharmacokinetic (PBPK) model for predicting oral bioavailability following RYGB. MethodsA single-dose pharmacokinetic study of metoprolol tartrate 200mg immediate release and controlled release was performed in 14 volunteers before and 6-8months after RYGB. The observed data were compared with predicted results from the PBPK modelling and simulation of metoprolol tartrate immediate and controlled-release formulation before and after RYGB. ResultsAfter administration of metoprolol immediate and controlled release, no statistically significant difference in the observed area under the curve (AUC(0-24h)) was shown, although a tendency towards an increased oral exposure could be observed as the AUC(0-24h) was 32.4% [95% confidence interval (CI) 1.36, 63.5] and 55.9% (95% CI 5.73, 106) higher following RYGB for the immediate and controlled-release formulation, respectively. This could be explained by surgery-related weight loss and a reduced presystemic biotransformation in the proximal gastrointestinal tract. The PBPK values predicted by modelling and simulation were similar to the observed data, confirming its validity. ConclusionsThe disposition of metoprolol from an immediate-release and a controlled-release formulation was not significantly altered after RYGB; there was a tendency to an increase, which was also predicted by PBPK modelling and simulation.