Published in AAPS PharmSciTech, this study examined the use of the beagle dog as a preclinical model for oral drug formulation. Despite physiological differences, dogs are often used to estimate relative bioavailability. However, variations in pH, bile salt concentration, and micellar structure between species can significantly affect solubility—especially for BCS Class II/IV compounds.
Researchers evaluated solubility using FaSSIFc, a canine fasted simulated intestinal fluid designed to mirror the luminal environment of a fasted beagle. Solubility results from FaSSIFc were compared with those from human FaSSIF across several preclinical drug candidates.
For free bases and neutral compounds, solubility followed predictable patterns based on sodium taurocholate concentration. In contrast, weak acids displayed dramatically higher solubility in FaSSIFc due to the dog’s higher intestinal pH and increased bile salt concentration. This species-specific effect means that weak acids may appear more soluble—and therefore more bioavailable—in dogs than in humans.
For one model compound, the authors demonstrated that the unexpectedly high solubility in dogs necessitated testing at higher doses to approximate human outcomes. Additionally, using FaSSIFc values improved physiologically based absorption model predictions of plasma concentration profiles in dogs.
Overall, these findings highlight the need for caution when relying on dogs to predict human pharmacokinetic performance for weak acids. Detailed solubility measurements and species-appropriate modeling are essential to avoid misleading conclusions in formulation development.
Source: Walsh, P. L., Stellabott, J., & colleagues (2016). Comparing Dog and Human Intestinal Fluids: Implications on Solubility and Biopharmaceutical Risk Assessment. AAPS PharmSciTech. Published September 6, 2016.
