Factors Influencing the Use and Interpretation of Animal Models in the Development of Parenteral Drug Delivery Systems

Abstract

Abstract. Depending upon the drug and drug delivery platform, species-specific physiological differences can lead to errors in the interspecies extrapolation of drug performance. This manuscript provides an overview of the species-specific physiological variables that can influence the performance of parenteral dosage forms such as in situ forming delivery systems, nanoparticles, microspheres, liposomes, targeted delivery systems, lipophilic solutions, and aqueous suspensions. Also discussed are those factors that can influence the partitioning of therapeutic compounds into tumors, the central nervous system and the lymphatics. Understanding interspecies differences in the movement and absorption of molecules is important to the interpretation of data generated through the use of animal models when studying parenteral drug delivery.

Bioequivalence accomplishments, ongoing initiatives, and remaining challenges

“…This was accomplished in May, 2010. The convening of a BE Workshop as a platform for dialog on the challenges encountered when evaluating product BE for veterinary pharmaceuticals. This event occurred on June, 2010 ( http://aavpt.affiniscape.com/associations/12658/files/BEWorkshopfinalagenda6-4-10.pdf. Publication of a workshop summary report (Martinez et al ., ). Development of white papers by working groups representing experts from across the globe. These white papers were published in a 2012 Supplemental Issue of the Journal of Veterinary Pharmacology and Therapeutics (JVPT; Fig.…”

“…Interspecies differences in the relative bioavailability of parenterally administered products have been shown to occur (Lifschitz et al ., ; Martinez et al ., ). Potential reasons for such differences include (Martinez, ):…”

“…Interspecies differences in the relative bioavailability of parenterally administered products have been shown to occur (Lifschitz et al, 1999;Martinez et al, 2001). Potential reasons for such differences include (Martinez, 2011): • Hot melt viscosity ○ differences in injection site physiology; ○ fluid composition; ○ fluid volumes; ○ lymphatic and vascular composition of the injection site; ○ muscle movements; ○ inflammatory responses; ○ differences in injected volumes. Published (2013).…”

Ex vivo binding of the immunosuppressant mycophenolic acid to dog and cat plasma proteins and the effect of co‐incubated dexamethasone and prednisolone

“…Several biological factors (e.g., albumin variants, fatty acids, etc.) may introduce dispersion in the extent of drug-protein binding among animals (Takamura, Maruyama, & Otagiri, 1997;Ito, Takahashi, Sudo, & Sugiyama, 2009;Martinez, 2011). However, the exact reasons for this interindividual variability are unclear.…”

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

“…However, it becomes more and more evident that animal-derived pharmaco-/toxicokinetic data are not always reliable for extrapolation to human safety assessment due to interspecies differences in physiology as well as in biochemical and metabolic pathways. Low-throughput, high costs and ethical considerations are further limitations associated with the use of animals (see also requirements in EU Directive 2010/63/EU on the protection of animals used for scientific purposes (Martinez, 2011)). To reduce animal experimentation and also the risk of failure of many drug candidates in the later phases of clinical trials, attempts have been made to provide inexpensive and convenient intestinal functional ex vivo and in vitro models to study toxicity and bioavailability of new substances and to study interactions between the host, pathogens and intestinal microflora.…”