Abstract
Despite many documented differences in gut physiology compared to humans, the beagle dog has been successfully used as a preclinical model for assessing the relative bioavailability of dosage forms during formulation development. However, differences in pH and bile salt concentration and micellar structure between dog and human intestinal fluids may influence the solubility and dissolution behavior of especially BCS II/IV compounds. Recently, a canine fasted simulated intestinal fluid (FaSSIFc) mimicking the composition in the lumen of the beagle dog under the fasted state has been proposed. In this manuscript, we present the utilization of FaSSIFc to compare solubility of several preclinical candidates against human FaSSIF. While solubility of free bases and neutral compounds was easily predicted by the relative amounts of sodium taurocholate in the fluids, free acids were shown to be much more soluble in FaSSIFc owing to both the solubility at higher pH as well as the increased bile salt concentration. For one of the model compounds, we demonstrate that the high solubility necessitates the need for a formulation comparison at a relatively higher dose in the dog to mimic the outcome of a human relative bioavailability study. Finally, we show how using the solubility value in FaSSIFc for the same compound results in better predictability of the plasma concentration profiles in dogs from a physiologically based absorption model. The collective data indicate that caution and more detailed measurements are required if the dog is used as the preclinical model for the development of formulations of weak acids.
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The authors would like to thank Lan Jin, Kim Manser, and Becky Nissley for their support of this project.
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All animal study protocols were reviewed and approved by the Merck IACUC (Institutional Animal Care and Use Committee). The Guide and Animal Welfare regulations were followed in the conduct of the animal studies. Veterinary care was given to any animals requiring medical attention.
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Walsh, P.L., Stellabott, J., Nofsinger, R. et al. Comparing Dog and Human Intestinal Fluids: Implications on Solubility and Biopharmaceutical Risk Assessment. AAPS PharmSciTech 18, 1408–1416 (2017). https://doi.org/10.1208/s12249-016-0611-2
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DOI: https://doi.org/10.1208/s12249-016-0611-2