Comparing Dog and Human Intestinal Fluids: Implications on Solubility and Biopharmaceutical Risk Assessment

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.

Impact of gastrointestinal differences in veterinary species on the oral drug solubility, in vivo dissolution, and formulation of veterinary therapeutics

“…For neutral molecules and weak bases with a pKa of less than 3, the difference is largely a function of the species-specific extent of bile micellization. Above pH 4, the human-canine differences in the solubility of weak acids appear to be associated with the extent to which solubilization occurs when the drug is in both its ionized and its unionized forms [ 61 ].…”

“…One might anticipate that these differences in intestinal components could lead to a greater ability to solubilize certain lipophilic drugs in dogs as compared to humans [ 9 ]. Furthermore, the intestinal buffering capacity (mM/ΔpH) of the fasted dog is slightly higher than that of fasted humans (13.8 versus 12 for dog and human, respectively) and the osmolality (mOsmol/kg) tends to be higher in humans as compared to dogs (181.6 versus 270 for dogs and humans, respectively) [ 61 ].…”

Comparison of Canine and Human Physiological Factors: Understanding Interspecies Differences that Impact Drug Pharmacokinetics

“…For neutral molecules and for weak bases with a pKa of less than 3, the difference was largely a function of the species-specific extent of bile micellization. Above pH 4, the solubility differences for weak acids were associated both with ionized and unionized drug solubilization (32).…”

“…The impact of bile salts on drug absorption may be drug and animal species specific (32,37). The recommended composition of canine fasted state simulated intestinal fluids (FaSSIFc) includes 5 mM sodium taurocholate and sodium taurodeoxycholate (34), while for humans, the recommendation is only 3 mM sodium taurocholate (38).…”

Automated Supersaturation Stability Assay to Differentiate Poorly Soluble Compounds in Drug Discovery

“…Species-specific simulated intestinal media have recently been proposed and generally demonstrate higher solubility than FaSSIF. 25,26 However, if a compound does not demonstrate either acceptable thermodynamic solubility or supersaturation stability in FaSSIF, it may represent a worst case scenario and flag development risk moving forward into higher species including human. It is also feasible to increase the DMSO stock concentration to evaluate higher dynamic ranges (>250 mM), as well as target a specific range above the equilibrium solubility.…”