(T1530-03-15) In Vitro Evaluation of Drug Concentrations in the Contents of Upper Gastrointestinal Lumen During the Post-Disintegration Period in the Fed State: Design and Performance Assessment of BioGITfed

Purpose: To design and implement a biorelevant gastrointestinal transfer system (BioGITfed) for evaluating the concentrations of highly permeable drugs during their transfer from the antrum through upper small intestine after a high-calorie, high-fat meal. To assess the usefulness of BioGITfed in the evaluation of luminal concentrations of paracetamol and danazol during the drug transfer process from the antrum through the upper small intestine.

Methods: BioGITfed was designed by assuming apparent first-order kinetics for the drug transfer from the antrum through the upper small intestine and practically unchanged apparent volume of contents in the antrum and in the upper small intestine during the first three hours of the transfer process (Dietrich et al. 2024). BioGITfed was implemented in vitro as a four-compartment system consisting of a gastric reservoir compartment, a gastric compartment, a duodenal reservoir compartment, and a flow-through duodenal compartment. The in vitro testing conditions were based on the best estimates for the volume of contents of the antrum and of the upper small intestine, the antral emptying half-life, and the half-life of drug elimination from the upper small intestine (Dietrich et al. 2024). The relative standard deviation (RSD) of the data and their bias from the theoretically expected values were used to evaluate the robustness of the system by using paracetamol as model drug, Level III FeSSGF_HCl (Chorianopoulou et al. 2023) in the gastric compartment and Level II FeSSIF-V2 (Markopoulos, Andreas et al 2015) in the duodenal compartment. BioGITfed was then evaluated for its usefulness in simulating total danazol amount per volume of contents in the gastric contents and in the aspirates from the upper small intestine and danazol concentrations in the non-oily phase of gastric contents [collected previously after ultracentrifugation of antral aspirates (Pentafragka et al. 2020) and in the micellar phase of aqueous contents of upper small intestine [collected previously after ultracentrifugation of aspirates from the upper small intestine (Pentafragka et al. 2020), as a function of time after administration of danazol particles at the antral region in the fed state.

Results: Transfer of paracetamol was achieved reproducibly at all sampling time points (RSD ≤4.92% and RSD ≤ 18.02 % for the data in gastric and in the duodenal compartment, respectively) and according to the theoretically expected values (Bias ≤ 9.43%). Total danazol amount per volume were reproducible (RSD < 14.3 % and RSD < 14.6 % for the data in gastric and in the duodenal compartment, respectively) and in line with previously reported data in adults (Pentafragka et al. 2020). Danazol concentrations in the non-oily phase of the gastric compartment and in micellar phase of aqueous contents of the duodenal compartment were in line with previously reported concentrations in the non-oily phase of gastric contents and in the micellar phase of aqueous contents of the upper small intestine (Pentafragka et al. 2020).

Conclusion: BioGITfed was implemented successfully and provided biorelevant gastric and duodenal drug concentrations of paracetamol and danazol during their transfer from the antrum through upper small intestine after a high-calorie, high-fat meal.

References: Chorianopoulou et al. PharmSci 360, AAPS Annual Meeting, October 22-25, 2023, Orlando, USA (poster).
Dietrich et al. J Pharm Sci (in press) doi: 10.1016/j.xphs.2024.01.001.
Markopoulos et al. J. Pharm. Sci. 104:2986-2997 (2015).
Pentafragka et al. Eur. J. Pharm. Sci. 149:105351 (2020).

Acknowledgements: This work was partially funded by the European Union’s Horizon 2020 research and innovation programme (https://www.inpharma-network.eu/) under the Marie Skłodowska-Curie grant agreement No 955756