The pig as a preclinical model for predicting oral bioavailability and in vivo performance of pharmaceutical oral dosage forms: a PEARRL review

In addition to metabolic differences, the anatomical, physiological, and biochemical differences in the gastrointestinal (G.I.) tract of the human and common laboratory animals can cause significant variation in drug absorption from the oral route. Among the physiological factors, pH, bile, pancreatic juice, and mucus and fluid volume and content can modify dissolution rates, solubility, transit times, and membrane transport of drug molecules. The microbial content of the G.I. tract can significantly affect the reductive metabolism and enterohepatic circulation of drugs and colonic delivery of formulations. The transit time of dosage forms can be significantly different between species due to different dimensions and propulsive activities of the G.I. tract. The lipid/protein composition of the enterocyte membrane along the G.I. tract can alter binding and passive, active, and carrier-mediated transport of drugs. The location and number of Peyer's patches can also be important in the absorption of large molecules and particulate matter. While small animals, rats, mice, guinea pigs, and rabbits, are most suitable for determining the mechanism of drug absorption and bioavailability values from powder or solution formulations, larger animals, dogs, pigs, and monkeys, are used to assess absorption from formulations. The understanding of physiological, anatomical, and biochemical differences between the G.I. tracts of different animal species can lead to the selection of the correct animal model to mimic the bioavailability of compounds in the human. This article reviews the anatomical, physiological, and biochemical differences between the G.I. tracts of humans and commonly used laboratory animals.

In vitro screening for drugs that inhibit cytochrome P450 enzymes is well established as a means for predicting potential metabolism-mediated drug interactions in vivo. Given that these predictions are based on enzyme kinetic parameters observed from in vitro experiments, the miscalculation of the inhibitory potency of a compound can lead to an inaccurate prediction of an in vivo drug interaction, potentially precluding a safe drug from advancing in development or allowing a potent inhibitor to 'slip' into the patient population. Here, we describe the principles underlying the generation of in vitro drug metabolism data and highlight commonly encountered uncertainties and sources of bias and error that can affect extrapolation of drug-drug interaction information to the clinical setting.

In this article we review the value and utility of the minipig as an animal model in regulatory toxicity testing. Our review is based on detailed consideration of the comparative biology of the minipig, and of the practical features of toxicity testing in the minipig. The minipig presents a favourable profile as a non-rodent toxicology model, in terms of the similarity to man and also in terms of applicability to different study types. Studies of general toxicology can be performed in the minipig by oral, cutaneous, parenteral and inhalation routes. For reproductive toxicology studies the minipig offers numerous advantages as a non-rodent model although the lack of placental transfer of macromolecules may limit the role of the minipig in reproductive testing of biotechnology products. For safety pharmacology studies the minipig is an advantageous model, particularly as regards the cardiovascular system. The immune system of the pig is better characterized than that of the dog, making the pig an interesting alternative model to the nonhuman primate for therapeutic approaches based on manipulation of the immune system. Overall, this review leads us to believe that the minipig might be a better non-rodent toxicology model than the dog. At the present time, however, insufficient comparative data is available to permit a rigorous evaluation of the predictivity of the minipig for human drug-induced toxicities and research is urgently needed to provide experimental data for evaluation of the hypothesis that minipig studies may better reflect human drug-induced toxicities than studies performed in traditional non-rodent toxicology models. It would be of particular value to gain a better vision of the potential utility of the minipig as a model for the safety testing of new biologics, where the minipig could potentially replace the use of non-human primates in the testing of some new products. Copyright © 2010 Elsevier Inc. All rights reserved.