CJ-023,423 (Grapiprant) a Potential Novel Active Compound with Antihyperalgetic Properties for Veterinary Patients

Vet Pharm & Therapeutics

Owen

et al. 2017

Drugs that provide effective analgesia in cats are limited. The aim of the study was to assess the pharmacokinetics of grapiprant after 2 mg/kg administration via p.o. and i.v. routes in cats. Six healthy adult cats were used according to an open, single-dose, two-treatment, two-period, randomized cross-over design. Cats were assigned to two treatment groups and administered with 2 mg/kg of grapiprant (pure powder) through p.o. and i.v. administration. Blood samples were collected at preassigned times and analysed by a validated HPLC method. After both administrations, grapiprant concentrations were detectable in plasma for up to 24 hr in five of six animals. The critical parameters including clearance (173.2 ml hr kg , range 120-326 ml hr kg ) and volume of distribution (918 ml/kg, range 611-1608 ml/kg) were calculated from the i.v. group. The mean oral F% was low (39.6% range 31.5%-45.2%). If the assumption that the minimal effective concentration in dogs (164 ng/ml) applies in cats too, grapiprant orally administered at 2 mg/kg might be effective for 10 hr. Further studies are necessary to establish the minimal effective concentration in this animal species.

Section: Introductionmentioning

confidence: 99%

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

Łebkowska‐Wieruszewska

Vet Pharm & Therapeutics

Owen

et al. 2017

“…There is great potential for use of grapiprant in veterinary species (Giorgi, ). Its PK profiles have been already published in dogs (Lebkowska‐Wieruszewska et al ., ; Nagahisa & Okumura, ) and cats (Rausch‐Derra & Rhodes, ), but no PK or PD profiles have been assessed in rabbits.…”

Section: Discussionmentioning

confidence: 99%

“…The EP4 receptor is not the only receptor involved in inflammation and pain, but its inhibition may mediate central sensitization and play a role in pain in humans and animals (Lin et al, 2006;Nakao et al, 2007). Grapiprant has been recently approved by FDA for use in canine medicine (Giorgi, 2015). Studies have already determined its good safety and efficacy profiles in dogs (Rausch-Derra et al, 2016a), and its pharmacokinetics at high doses have been investigated in dogs and cats (Rausch-Derra & Rhodes, 2016;Rausch-Derra et al, 2016b).…”

Section: Introductionmentioning

confidence: 99%

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

Vet Pharm & Therapeutics

Salvadori²,

Poapolathep

et al. 2016

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.

“…Since grapiprant is an under development drug at advanced stage [7] an easy and accurate method for its detection in plasma is needed for pharmacokinetic studies. The aim of the present study was twofold: i) to develop an easy and sensitive method to quantify grapiprant in canine plasma, ii) to apply the optimized method for the detection of its pharmacokinetics in a dog.…”

Section: Cj-023423 1-[2-[4-(2-ethyl-46-dimethylimidazo[45-c]pyridimentioning

confidence: 99%

Detection and quantification of the selective EP4 receptor antagonist CJ-023423 (grapiprant) in canine plasma by HPLC with spectrofluorimetric detection

Journal of Pharmaceutical and Biomedical Analysis

Lee

Owen

et al. 2016

Self Cite

Detection and quantification of the selective EP4 receptor antagonist CJ-023423 (grapiprant) in canine plasma by HPLC with spectrofluorimetric detection, Journal of Pharmaceutical and Biomedical Analysis http://dx.doi.org/10.1016/j.jpba. 2015.11.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HighlightsGrapiprant is a new active ingredient under development for the control of pain and inflammation A validated HPLC method with spectrofluorimetric detection has been developedThe chromatographic runs were specific with no interfering peaks at the retention times of the analyte and IS LOD and LLOQ were 3 and 10 ng/ml This method is suitable for pharmacokinetic investigations such as guiding dose adjustment 4 Abstract Grapiprant, a novel pharmacologically active ingredient, acts as a selective EP4 receptor antagonist whose physiological ligand is prostaglandin E2 (PGE2). It is currently under development for use in humans and dogs for the control of pain and inflammation associated with osteoarthritis. The aim of the present study was to develop an easy and sensitive method to quantify grapiprant in canine plasma and to apply the method in a canine patient. Several parameters, both in the extraction and detection method were evaluated. The final mobile phase consisted of ACN:AcONH4 (20 mM) solution, pH 4 (70:30, v/v) at a flow rate of 1 mL/min. The elution of grapiprant and IS (metoclopramide) was carried out in isocratic mode through a Synergi Polar-RP 80A analytical column (150 mm × 4.6 mm). The best excitation and emission wavelengths were 320 and 365 nm, respectively. Grapiprant was extracted from the plasma using CHCl3, which gave a recovery of 88.1 ± 10.22% and a lower limit of quantification (LLOQ) of 10 ng/mL. The method was validated in terms of linearity, limit of detection (LOD), LLOQ, selectivity, accuracy and precision, extraction recovery, stability, and inter-laboratory cross validation, according to international guidelines. The chromatographic runs were specific with no interfering peaks at the retention times of the analyte and IS, as confirmed by HPLC-MS experiments.In conclusion, this was a simple and effective method using HPLC-FL to detect grapiprant in plasma, which may be useful for future pharmacokinetic studies.