Species Differences in Metabolism of Soluble Epoxide Hydrolase Inhibitor, EC1728, Highlight the Importance of Clinically Relevant Screening Mechanisms in Drug Development.

Cindy B Mcreynolds,Sung Hee Hwang,Heather Knych,Bruce D Hammock,Briana Hamamoto,Caitlin Tearney,Christophe Morisseau,Jun Yang,Karen Wagner,Roberto Garcia,Alonso Guedes

doi:10.3390/molecules26165034

Abstract

There are few novel therapeutic options available for companion animals, and medications rely heavily on repurposed drugs developed for other species. Considering the diversity of species and breeds in companion animal medicine, comprehensive PK exposures in the companion animal patient is often lacking. The purpose of this paper was to assess the pharmacokinetics after oral and intravenous dosing in domesticated animal species (dogs, cats, and horses) of a novel soluble epoxide hydrolase inhibitor, EC1728, being developed for the treatment of pain in animals. Results: Intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50% F) but lower in mice and cats (34 and 8%, respectively). Additionally, clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses. Efficacy with EC1728 has been demonstrated in mice, dogs, and horses, and despite the rapid clearance of EC1728 in cats, analgesic efficacy was demonstrated in an acute pain model after intravenous but not oral dosing. Conclusion: These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity.

Highlights

The PK profile of EC1728 was similar between most species with some important differences: intravenous and oral administration revealed that bioavailability was similar for dogs, and horses (42 and 50%F) but lower in mice and cats (34 and 8%, respectively)
Clearance was similar between cats and mice, but >2× faster in cats vs. dogs and horses
Despite the faster clearance, EC1728 demonstrated efficacy in an acute pain model in cats after IV but not PO administration. These results demonstrate that exposures across species can vary, and investigation of therapeutic exposures in target species is needed to provide adequate care that addresses efficacy and avoids toxicity

Summary

Introduction

Companion animal medications are often repurposed drugs approved for human use or for use in species other than the patient being treated [1]. More research is being conducted to understand exposures in companion animals, information is still lacking, and limited understanding of the distribution and pharmacokinetic profiles of compounds in the intended species can result in failed efficacy from conservative dosing strategies used to avoid toxicities. Due to the paucity of data, dose recommendations are often based on allometric scaling and in-vitro metabolic stability in microsomes; this may not capture true metabolism if other mechanisms of elimination, such as intestinal transporters or phase II metabolism, are involved [2]. The broad generalizations of exposure based on human data or data in other species are especially problematic for cats. Cats are obligate carnivores and have fewer mechanisms for xenobiotic metabolism as a result [3,4]

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