Pharmacology of grapiprant, a novel <scp>EP</scp>4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs

<jats:p>Grapiprant is an analgesic and anti‐inflammatory drug in the piprant class that was approved in March 2016 by <jats:styled-content style="fixed-case">FDA</jats:styled-content>'s Center for Veterinary Medicine for the control of pain and inflammation associated with osteoarthritis (<jats:styled-content style="fixed-case">OA</jats:styled-content>) in dogs. Grapiprant functions as a selective antagonist of the <jats:styled-content style="fixed-case">EP</jats:styled-content>4 receptor, one of the four prostaglandin E<jats:sub>2</jats:sub> (<jats:styled-content style="fixed-case">PGE</jats:styled-content><jats:sub>2</jats:sub>) receptor subtypes. The <jats:styled-content style="fixed-case">EP</jats:styled-content>4 receptor mediates <jats:styled-content style="fixed-case">PGE</jats:styled-content><jats:sub>2</jats:sub>‐elicited nociception, and grapiprant has been shown to decrease pain in several rat inflammatory pain models. It was also effective in reducing pain associated with <jats:styled-content style="fixed-case">OA</jats:styled-content> in humans, providing evidence for its mechanism of action in these species. The estimated canine efficacy dose of between 1.3 and 1.7 mg/kg, p.o. with a methylcellulose suspension, once a day, was predicted based on calculations from comparative affinity of grapiprant to the dog, rat, and human <jats:styled-content style="fixed-case">EP</jats:styled-content>4 receptors, serum protein binding, effective doses defined in rat models of pain and inflammation, and human clinical studies. The results of this study guided the doses to be tested in the pilot study and demonstrated the usefulness of the efficacy dose prediction method. The approved commercial tablet dose of grapiprant is 2 mg/kg once a day for the control of pain and inflammation associated with <jats:styled-content style="fixed-case">OA</jats:styled-content> in dogs.</jats:p>