Physiologically Based Absorption Modeling of Salts of Weak Bases Based on Data in Hypochlorhydric and Achlorhydric Biorelevant Media
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Physiologically based absorption modeling has been attracting increased attention to study the interactions of weakly basic drug compounds with acid-reducing agents like proton-pump inhibitors and H2 blockers. Recently, standardized gastric and intestinal biorelevant media to simulate the achlorhydric and hypochlorhydric stomach were proposed and solubility and dissolution data for two model compounds were generated. In the current manuscript, for the first time, we report the utility of these recently proposed biorelevant media as input into physiologically based absorption modeling. Where needed, data collected with the biorelevant gastrointestinal transfer (BioGIT) system were used for informing the simulations in regard to the precipitation kinetics. Using two model compounds, a HCl salt and a semi-fumarate co-crystal which as expected dissolve to a greater extent in these media (and in gastric and intestinal human aspirates) compared to what the pH–solubility profile of the free form would suggest, we demonstrate successful description of the plasma concentration profiles and correctly predicted the lack of significant interaction after administration with pantoprazole or famotidine, respectively. Thus, the data reported in this manuscript represent an initial step towards defining biorelevant input for such simulations on interactions with acid-reducing agents.
KEY WORDSphysiologically based absorption modeling hypochlorhydria achlorhydria biorelevant media GastroPlus
Authors would like to thank Ms. Chara Litou for her contribution to the BioGIT experiments. Part of the work presented in this manuscript was presented at the annual EDAN meeting, Leuven, Belgium, 11–13 March 2018.
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