Guy Bouchard

The Miniature Swine as a Model in Experimental and Translational Medicine

The use of the miniature swine as a nonrodent species in research has continued to expand for over a decade, and they are becoming routinely used both in experimental pharmacology and as a therapeutic model for human diseases. Miniature swine models are regularly used for studies designed to assess efficacy and safety of new therapeutic compounds given through different routes of exposure and are used as an alternative model to rodents, canines, or nonhuman primates. Translational preclinical swine study data presented here support the current understanding that miniature swine are the animal model of choice for the assessment of drugs targeting endocrine, dermal, and ocular disorders. Because research investigators need to be familiar with some of the important features of the models developed in the miniature swine in order to place clinical and experimental findings in their proper perspective, relevant references and data from these models will be presented, compared, and partially illustrated.

Miniature Swine Breeds in Toxicology and Drug Safety Assessments What to Expect during Clinical and Pathology Evaluations

The use of miniature swine as a nonrodent species in safety assessment has continued to expand for over a decade, and they are becoming routinely used in toxicology and in pharmacology as well as a model for human diseases. Miniature swine models are regularly used for regulatory toxicity studies designed to assess safety of new therapeutic compounds given through different routes of exposure and are used as an alternative model to the canine or the nonhuman primate. Translational preclinical swine study data presented support the current finding that miniature swine are the animal model of choice for assessment of drug absorption, tolerance, and systemic toxicity following systemic exposures. Because research investigators need to be familiar with important anatomic and histopathologic features of the miniature swine in order to place toxicopathologic findings in their proper perspective, clinical and anatomic pathology data from a large number of Sinclair, Hanford, Yucatan, and Göttingen breeds from control groups from a wide variety of studies performed between 2004 and 2014 will be presented, compared, and partially illustrated.

The importance of minipigs in dermal safety assessment: an overview.

Abstract The use of miniature swine as a non-rodent species in safety assessment has continued to expand for over a decade and their use has become routine, particularly in pharmacology as a model for human integumentary diseases. Translational preclinical swine study data are now favorably compared and contrasted to human data, and miniature swine models provide important information in dermal safety assessment and skin pharmacology. For example, the miniature swine model has been well-accepted for cutaneous absorption and toxicity studies due to swine integument being morphologically and functionally similar to human skin. Subsequently, this model is important to dermal drug development programs, and it is the animal model of choice for assessment of dermal absorption, local tolerance and systemic toxicity following dermal exposures. In conclusion, the miniature swine model has an important role to play in the safety assessment of pharmaceutical products and in multiple aspects of human dermal drug development.

Minipigs: Applications in Toxicology

Minipigs are accepted models for a variety of drug preclinical and nonregulatory toxicology studies. Acute, subchronic and chronic studies are possible using all routes of administration. Minipigs have distinct size advantages over domestic pigs. There exist some minor limitations with minipigs, but for the most part they offer well correlated models to humans for dermal and systemic toxicology assessments. Phototoxicology and reproductive toxicology usage is expanding. Minipig size, anatomy, physiology, metabolism, and genetics generally correlate well to human factors. The minipig makes an appropriate model for toxicology. Curr. Protoc. Toxicol. 56:1.11.1‐1.11.19.

Miniature swine model of phototoxicity testing.

This study determined the threshold doses for ‘solar erythema’ and for phototoxic responses to 8‐methoxypsoralen (8‐MOP) in white skin Hanford and grey skin Yucatan miniature swine.

Comparative cardiovascular physiology and pathology in selected lineages of minipigs: Relation to drug safety evaluation

The minipig has been increasingly recognized as a valid alternative to canines and nonhuman primates in regulatory toxicity. This article presents the results of cardiovascular assessments in the Yucatan, Hanford, Sinclair, and Göttingen minipigs conducted during nonclinical investigations and control toxicity testing. Cardiac electrophysiology was obtained using clinical electrocardiogram and surgical monitor units. Peripheral vessel diameter, velocity, and flow were obtained by Doppler ultrasonography, and cardiac vessel diameter was obtained postmortem. Anatomic parameters were obtained at necropsy. Histopathology assessments were conducted on heart, blood vessels, and kidneys. Collected data were compared to published cardiovascular measurements of adult humans to illustrate similarities and differences. Each lineage of minipigs was found to have specific anatomic and physiologic characteristics that may accurately reflect response of human cardiovascular systems in clinical investigations and toxicity testing. In conclusion, the interspecies similarities between the cardiovascular systems make these lineages of minipigs suitable as models for the human counterpart. In addition, these reported differences between lineages will aid investigators in selecting a relevant lineage of minipigs if specific cardiovascular parameters are required during drug safety evaluation.

Development of a Functional Observational Battery in the Minipig for Regulatory Neurotoxicity Assessments

A functional observational battery (FOB) is recommended as the first-tier neurotoxicity screening in the preclinical safety pharmacology testing guidelines. Minipigs have increasingly been used in regulatory toxicology studies; however, no current FOB protocol is available for neurotoxicity testing in these species. Hence, a minipig FOB instrument was developed. A complete crossover study with Sinclair minipigs was performed to evaluate physiologic, neurologic, and behavioral effects of amphetamine, ketamine, and diazepam. The treated minipigs were first observed in their home cage, were video-recorded for 10 minutes in an open field, and then went through a complete neurologic examination. Both ketamine and diazepam were shown to reduce the freezing and behavior shifts of treated minipigs, while increasing their exploratory behaviors. Both drugs also caused muscular and gait impairment. The effects of ketamine and diazepam were consistent with their roles as central nervous system (CNS) suppressants. Unique effects were also observed with ketamine and diazepam treatments, which may reflect their unique mechanisms of action. Consistent with its role as a CNS stimulant, amphetamine caused the treated minipigs to be hyperactive and to display increased freezing and behavior shifts and reduced exploring activities. These effects of amphetamine were opposite to those observed with ketamine and diazepam. Amphetamine also increased locomotion in the treated minipigs. The present effects of amphetamine, ketamine, and diazepam are in agreement with observations by others. In conclusion, the minipig is a suitable species for FOB evaluation of pharmaceuticals in preclinical safety pharmacology testing.