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

Abstract

Grapiprant is a prostaglandin E2 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 PGE2 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 PGE2 and determining TNF‐ɑ 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.

Comparison of grapiprant and meloxicam for management of postoperative joint pain in dogs: A randomized, double‐blinded, prospective clinical trial

“…However, the EP 4 receptor also plays a constitutive role in articular and bones tissues and PGE 2 is also involved in acute inflammation 10 . Additionally, grapiprant inhibits PGE 2 binding to EP 4 as soon as 2 to 4 hours after oral administration 22 . Its rapidity of action suggests that grapiprant could represent an interesting therapeutic option for the management of acute or subacute pain, in addition to its indication in chronic pathophysiological affections.…”

“… 10 Additionally, grapiprant inhibits PGE 2 binding to EP 4 as soon as 2 to 4 hours after oral administration. 22 Its rapidity of action suggests that grapiprant could represent an interesting therapeutic option for the management of acute or subacute pain, in addition to its indication in chronic pathophysiological affections. However, the use of grapiprant in indications other than light to moderate osteoarthritis is currently under debate.…”

Pharmacokinetics of a single oral dose of grapiprant in juvenile pigs (Sus scrofa domestica)

“…The PK profile of grapiprant has been also determined in cats (Lebkowska‐Wieruszewska, Lebkowska‐Wieruszewska, De Vito, et al, 2017), horses (Cox et al, 2020; Hoffmann et al, 2022; Knych et al, 2018), rabbits (De Vito et al, 2017) red‐tailed hawks (Rodriguez et al, 2021), and goat kids (Halleran et al, 2021) with PK parameters widely varying across species (Table 2). In this study, grapiprant rapidly achieved plasma concentrations with a mean T max of <1 h. This is similar to findings in dogs, cats, and horses where the mean T max was <2 h (Lebkowska‐Wieruszewska, Barsotti, et al, 2017; Lebkowska‐Wieruszewska, De Vito, et al, 2017).…”

The Clinical Pharmacology and Therapeutic Evaluation of Non-Steroidal Anti-Inflammatory Drugs in Adult Horses

“…Since the effective plasma concentration for analgesia in dogs has been determined to be 114-164 ng/mL, higher doses would likely be required in horses to achieve therapeutic effect [238]. Following a single oral administration of 15 mg/kg, grapiprant reached a mean Cmax of 327.5 ng/mL within a mean Tmax of 1 h, and a mean elimination half-life of 11.1 h was calculated [239]. Despite the prolonged elimination half-life of grapiprant, TNF-α stimulation was only noted for 2-4 h post drug administration, indicating that the pharmacodynamic effect of grapiprant is relatively short in the horse [239].…”