Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit

Abstract

Grapiprant is the novel selective EP4 receptor inhibitor recently issued on the veterinary market for dogs affected by osteoarthritis. The aim of this study was twofold: to evaluate the pharmacokinetics and the pharmacodynamics of grapiprant in the induced inflammatory pain model in the rabbit after a single IV injection of 2 mg/kg; to compare the thermal antinociception effect after 2 mg/kg IV grapiprant, with that generated by 0.5 mg/kg meloxicam SC injected. Rabbits (n = 12) were randomly assigned to two crossover studies (single-dose, two-period crossover). The first study group A (n = 3) received a single IV dose of grapiprant at 2 mg/kg dissolved in ethanol. Group B (n = 3) received a single IV injection of ethanol (equivalent volume to grapiprant volume) at the same site. The second study group C (n = 3) received a single SC dose of meloxicam at 0.5 mg/kg. Group D (n = 3) received a single SC injection of 15% ethanol (equivalent volume to grapiprant volume) at the same site. After a 2-week washout period, the groups were rotated and the experiments repeated. Blood samples (0.7 mL) were collected from the right ear artery at assigned times and grapiprant plasma concentrations determined by a validated HPLC-FL method. Three hours prior to administration of the drugs, inflammation was induced by SC injection of lambda carrageenan (200 μL, 3% in physiological saline) under the plantar surface of the right hind paw. At a similar time to the blood collection, an infrared thermal stimuli (40 °C) was applied to the plantar surface of the rabbits' hindlimbs to evaluate the thermal withdrawal latency (TWL). The thermal antinociceptive effect was expressed as maximum possible response (% MPR). Grapiprant plasma concentrations were detectable up to the 10-h time point (concentration range 17-7495 ng/mL). The grapiprant-treated group showed a significant increase in TWL from 1 h and up to 10 h after drug administration compared to the control. In contrast, the meloxicam group showed a significant increase in TWL from 4 up to 10 h after drug administration, compared to control. The maximal MPR% was not statistically different between the grapiprant and meloxicam group from 4 to 8 h, while significant differences were shown at 1, 1.5, 2, 10 and 24 h. Given these findings, grapiprant appears to be an attractive option for antinociception in rabbits, due to its rapid onset and extended duration of effect.

Pharmacokinetics of grapiprant, a selective EP4 prostaglandin PGE2 receptor antagonist, after 2 mg/kg oral and i.v. administrations in cats

“…However, care with these data is needed because it is recognized that there may be some discrepancy between plasma concentration and actual effect at the receptor level (Toutain & Lees, ). Indeed a recent study found a protracted effect of grapiprant in the rabbit suggesting the generation of an active metabolite or a slow dissociation from the receptor (De Vito et al., ). Notably, the pharmacokinetic–pharmacodynamic hysteresis loop could be different in diverse species, and parameters, such as the onset time and time over the MEC, should be verified with ad hoc pharmacokinetic–pharmacodynamic studies.…”

“…Grapiprant is identified as a competitive antagonist of prostanoid EP 4 receptors with similar potency in humans, rats (Nakao et al., ) and in dogs (Nagahisa & Okumura, ). A randomized multisite clinical study has shown grapiprant as being effective for alleviation of pain in dogs with osteoarthritis, and a recent study has shown its effectiveness (comparable to meloxicam) in a carrageenan inflammatory model in the rabbit (De Vito et al., ). A recent study (Rausch‐Derra & Rhodes, ) reported very few toxicokinetic parameters and no concentration versus time profile curves in cats.…”

Dietary Supplementation with Palmitoyl-Glucosamine Co-Micronized with Curcumin Relieves Osteoarthritis Pain and Benefits Joint Mobility

“…Carrageenan (CAR)-induced inflammation is a recognized and highly reproducible model of acute inflammation and inflammatory pain [ 39 , 40 ]. Briefly, rats were anesthetized with 5.0% isoflurane in 100% O2 (Baxter International, Rome, Italy) and received a subplantar injection of carrageenan (CAR, 0.1 ml/rat of a 1% suspension in saline) (Sigma-Aldrich, Milan, Italy) with a 27-gauge needle into the right hind paw, as previously described [ 40 , 41 ].…”

Grapiprant: A snapshot of the current knowledge

“…A number of analytical methods for the quantification of grapiprant in different biological matrices have been published (Baralla et al, 2018 ; Cox et al, 2020 ; De Vito et al, 2016 , 2017 ; Heit et al, 2018 ; Knych et al, 2018 ; Łebkowska‐Wieruszewska et al, 2017 ; Nagahisa & Okumura, 2017 ). The devices used for the quantification of grapiprant are HPLC and LC‐MS/MS.…”

“…The pharmacokinetics of grapiprant after 2 mg/kg IV administration were described (De Vito et al, 2017 ). Grapiprant plasma concentrations were detectable up to the 10‐h time point (concentration range 17–7495 ng/ml).…”