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Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan‐induced inflammatory pain model in the rabbit
Author(s) -
De Vito V.,
Salvadori M.,
Poapolathep A.,
Owen H.,
Rychshanova R.,
Giorgi M.
Publication year - 2017
Publication title -
journal of veterinary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.527
H-Index - 60
eISSN - 1365-2885
pISSN - 0140-7783
DOI - 10.1111/jvp.12380
Subject(s) - meloxicam , pharmacodynamics , pharmacokinetics , crossover study , anesthesia , saline , chemistry , pharmacology , carrageenan , medicine , alternative medicine , pathology , placebo
Grapiprant is the novel selective EP 4 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.