ICH guidelines require the use of two species in nonclinical studies for pharmaceuticals, including one rodent and one non-rodent species. With its many anatomical, physiological and functional similarities to humans, the miniature pig (minipig, Sus scrofa) has become a viable alternative to non-rodent animal models in nonclinical safety testing.

While the minipig is subject to the same ethical and humane care concerns as other non-rodent species, its use in nonclinical safety testing appears to be more acceptable to the general public. In addition, there are many cases in which this animal is considered the most appropriate model from a scientific perspective.

Minipig Strains and the Emergence of the Göttingen Minipig

Among the strains of miniature swine available for nonclinical studies are the Göttingen minipig, the Hanford minipig, the Yucatan minipig and micropig, the Troll minipig and the Sinclair minipig.

The Göttingen minipig originated at the University of Göttingen (Germany) in the 1960’s as a result of crossbreeding the Vietnamese swine, the Hormel or Minnesota miniature swine and the German-improved Landrace. Due to the Göttingen minipig’s small stature, relatively calm demeanor and suitability for most testing purposes, it has rapidly become the mainstay for nonclinical testing in miniature pigs.

Göttingen minipigs reach sexual maturity at a considerably earlier age than the standard, non-rodent species used in drug safety studies, with boars reaching maturity at 3-4 months and sows at 4-5. At the age that minipigs are commonly used in drug safety studies (~3-4 months) the animals approach maturity by the end of 28-day studies and achieve complete maturity by the end of 13-week studies.

The Minipig in Nonclinical Safety Studies

Initially, minipigs were used as the large animal species for safety testing in the development of dermal pharmaceutical products. This was due to the fact that, compared to other non-rodent species, the skin of this animal more closely resembles humans in many respects, including sparse distribution of the hair coat, overall histologic appearance, epidermal thickness, keratinocyte turnover time, xenobiotic metabolic activity, and similar dermal penetration rates for many chemicals. In addition to the dermal route of administration, minipigs are easily dosed via the oral (gavage or capsule), intravenous and subcutaneous routes.

Moreover, there are many cases in which minipigs are suitable alternatives to the standard non-rodent species because of species-specific, dose-limiting toxicity to drugs of certain classes or drug vehicles. Examples of drug classes include cytotoxic anticancer drugs and non-steroidal anti-inflammatory drugs (NSAIDs). Minipigs are also refractory to anaphylactoid responses following intravenous injections of certain vehicles (e.g. Tween 80 and Cremophor EL).

Relative to other non-rodent species, perhaps the greatest limitation of the minipig is its physical size, which in most cases requires greater quantities of test article as well as poses technical challenges when handling older animals. The use of the minipig in nonclinical safety applications continues to grow every year, however. With greater characterization of the minipig model and ever-expanding historical control databases, the minipig is poised to replace standard, non-rodent species in many pharmaceutical development programs.
 

References

  1. Bode, G., et al.  The utility of the minipig as an animal model in regulatory toxicology.  J. Pharmacol. Toxicol. Methods 62: 196–220, 2010.
  2. Ellegaard, L., et al.  Welfare of the minipig with special reference to use in regulatory toxicology studies.  J. Pharmacol. Toxicol. Methods 62: 167–183, 2010.
  3. Lehman, H.  The minipig in general toxicology.  Scand. J. Lab. Anim. Sci., Suppl. 1., Vol. 25:  59-62, 1998.
  4. Mortensen J.T., et al.  The minipig in dermal toxicology.  A Literature Review. Scand. J. Lab. Anim. Sci., Suppl. 1., Vol. 25:  77-83, 1998.
  5. Swindle, M.M., et al.  Biology and Medicine of Swine.  In: Laboratory Animal Medicine and Management, J.D. Reuter and M.A. Suckow (Eds.).  International Veterinary Information Service, Ithaca, NY.  2003.
  6. Van der Laan, J.W., et al.  Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products.  J. Pharmacol. Toxicol. Methods 62: 184–195, 2010.