Influence of stereoselective pharmacokinetics in the development and predictability of an IVIVC for the enantiomers of metoprolol tartrate.

PURPOSE

To investigate the ability of an IVIVC developed with a racemate drug as well as each enantiomer in predicting the in vivo enantiomer drug performance.

METHODS

Dissolution of metoprolol extended release tablets with different release characteristics (e.g., fast (F), moderate (M), and slow (S)) was performed using USP Apparatus I, pH 1.2, 50 rpm. Metoprolol racemate tablets (S, M, and F, 100 mg) and 50 mg oral solution were administered to healthy volunteers, blood samples were collected over 24 (solution) and 48 (tablet) hours and assayed. IVIVC models developed were: (1) Racemate-fraction of drug dissolved (FRD) vs Racemate-fraction of drug absorbed (FRA), (2) R-FRD vs R-FRA, and (3) S-FRD vs S-FRA for combinations of formulations (S/M/F, S/M, S/F, and M/F). Enantiomer Cmax and AUC prediction errors (PEs) were estimated for model evaluation after convolution of in vivo release rates.

RESULTS

The R-IVIVC and S-IVIVC accurately predicted the R- and S-metoprolol pharmacokinetic profiles, respectively. The averaged prediction errors (PE) for the enantiomer Cmax and AUC were less than 10% for S/M/F, M/F, and S/F IVIVC models. Racemate-IVIVC (M/F) was able to predict S-enantiomer with an average %PE of 2.52 for S-Cmax and 4.3 for S-AUC. However, the racemate-IVIVC was unable to predict the R-enantiomer pharmacokinetic profile.

CONCLUSIONS

Metoprolol racemate data cannot be used to accurately predict R-enantiomer drug concentrations. However, the racemate data was predictive of the active stereoisomer.