Pharmacokinetics of grapiprant and effects on TNF-alpha concentrations following oral administration to horses

Grapiprant is a prostaglandin E-2 receptor antagonist that has been found to be an effective anti-inflammatory in dogs and that is devoid of some of the adverse effects associated with traditional NSAIDs that elicit their effects through inhibition of PGE(2) production. Previously published reports have described the pharmacokinetics of this drug in horses when administered at 2 mg/kg; however, pharmacodynamic effects in this species have yet to be described. The objective of the current study was to describe the pharmacokinetics and pharmacodynamics of grapiprant at a higher dose. Eight horses received a single oral administration of 15 mg/kg. Plasma concentrations were determined for 96 h using liquid chromatography-tandem mass spectrometry. Non-compartmental analysis was used to determine pharmacokinetic parameters. Pharmacodynamic effects were assessed ex vivo by stimulating blood samples with PGE(2) and determining TNF-alpha concentrations. Maximum concentration, time to maximum concentration and area under the curve were 327.5 (188.4-663.0) ng/ml, 1 (0.75-2.0) hour and 831.8 (512.6-1421.6) h*ng/ml, respectively. The terminal half-life was 11.1 (8.27-21.2) hr. Significant stimulation of TNF alpha was noted for 2-4 h post-drug administration. Results of this study suggest a short duration of EP4 receptor engagement when administered at a dose of 15 mg/kg.