Comparing Dog and Human Intestinal Fluids: Implications on Solubility and Biopharmaceutical Risk Assessment.
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.
Merck Research Laboratories, 125 E. Lincoln Ave, Rahway, New Jersey, USA. Paul.walsh@merck.com.
Paul L
PL
Walsh
Merck Research Laboratories, 220 Sumneytown Pike, West Point, Pennsylvania, USA.
Joyce
J
Stellabott
Merck Research Laboratories, 220 Sumneytown Pike, West Point, Pennsylvania, USA.
Rebecca
R
Nofsinger
Merck Research Laboratories, 220 Sumneytown Pike, West Point, Pennsylvania, USA.
Wei
W
Xu
Merck Research Laboratories, 125 E. Lincoln Ave, Rahway, New Jersey, USA.
Dorothy
D
Levorse
Merck Research Laboratories, 220 Sumneytown Pike, West Point, Pennsylvania, USA.
Kendra
K
Galipeau
Merck Research Laboratories, 220 Sumneytown Pike, West Point, Pennsylvania, USA.
Filippos
F
Kesisoglou
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004339:Drug Compounding; D005215:Fasting; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D018570:Risk Assessment; D012995:Solubility
FaSSIF; beagle; preclinical species; predictive technologies