Dissolution media simulating the proximal canine gastrointestinal tract in the fasted state

Abstract

Human biorelevant media have been shown to be a useful tool in pharmaceutical development and to provide input for in silico prediction of pharmacokinetic profiles after oral dosing. Dogs, in particular Beagles, are often used as animal models for preclinical studies. Key differences in the composition of human and canine gastric and intestinal fluids are described in the literature and underscore the need to develop a discrete set of biorelevant media, adapted to the conditions of the proximal canine gastrointestinal (GI) tract, to improve forecast and interpretation of preclinical results using in vitro dissolution studies. Canine biorelevant media can also be used in the development of oral dosage forms for companion animals, which is a rapidly growing market. The compositions of Fasted State Simulated Gastric Fluid canine (FaSSGFc) and Fasted State Simulated Intestinal Fluid canine (FaSSIFc) are adapted to the physiological composition of the corresponding gastrointestinal fluids in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid, and free fatty acid content (in terms of concentration and reported subtypes). It was demonstrated that canine Fasted State Simulated Intestinal Fluid (FaSSIFc) is superior in predicting the solubility of model compounds in Canine Intestinal Fluid (CIF) compared to the human biorelevant media (FaSSIF and FaSSIF-V2). Two different versions of FaSSGFc, composed at pH 1.5 and pH 6.5, offer the possibility to design in vitro studies which correspond to the in vivo study design, depending on whether pentagastrin is used to decrease the gastric pH in the dogs or not. Canine biorelevant media can therefore be recommended to achieve more accurate forecasting and interpretation of pharmacokinetic studies of oral drug products in dogs.