The use of BioGIT system to assess the impact of dose and formulation on early exposure to low solubility drugs after oral administration

Abstract

Purpose: To evaluate the usefulness of the Biorelevant Gastrointestinal Transfer (BioGIT) system in assessing the impact of dose and formulation on early exposure of five lipophilic active pharmaceutical ingredients (APIs) by comparing in vitro data with previously collected plasma data in healthy adults. Methods: Lu 35-138 (HCl salt of weak base) was studied at three dose levels in a-hydroxypropyl-beta-cyclodextrin solution. Fenofibrate was studied at two dose levels in the form of a solid dispersion formulation. AZD2207 (hemi-1,5-naphthalenedisulfonate salt of weak base) was studied at three dose levels in the form of immediate release capsules. SB705498 (weak base) was studied in the form of immediate release tablets and capsules. Cyclosporine A was studied in the form of self-emulsifying drug delivery systems, Sandimmun® and Sandimmun® Neoral. Duodenal concentrations were estimated using the BioGIT system. AUC0-0.75h values were calculated from the apparent concentration versus time data in the duodenal compartment of the BioGIT system and were used for estimating early exposure. Differences in AUC0-0.75h values were evaluated versus differences in AUC0-1h and in AUC0-2h values calculated from previously collected individual plasma data in healthy adults. Results: The BioGIT system qualitatively identified the impact of dose and of formulation on early exposure in all cases. Quantitative prediction of the impact of dose was possible for the fenofibrate solid dispersion tablets. Although trends matched, slight underestimation of differences in early exposure was observed for the three weak bases. Overestimation of the impact of formulation in early exposure to cyclosporine was observed. Conclusions: The BioGIT system was useful for detecting the impact of dose and of formulation on early exposure to five model lipophilic APIs