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Case flow indicating how the safety (intent to treat) and per protocol populations were identified for the grapiprant and placebo treatment groups. *Some dogs were excluded for more than one reason. †Grapiprant group: ruptured cranial cruciate ligament. Placebo group: toe infection and fell down stairs. #Grapiprant group: histiocytic sarcoma and osteosarcoma (none in placebo group).
Source publication
Background:
This study evaluated the effectiveness and safety of grapiprant for treatment of pain in dogs with osteoarthritis (OA).
Hypothesis/objectives:
Grapiprant will relieve pain as measured by the owner's and veterinarian's evaluation of pain in dogs with OA. Another objective was evaluation of the safety of grapiprant.
Animals:
Two hund...
Context in source publication
Context 1
... primary evaluation of the effectiveness variable was conducted on a Per Protocol Population (PPP). The PPP was a subset of the ITT population and comprised those dogs without substantial protocol violations or missing assessments and as agreed to, based on a blinded review meeting with Center for Veterinary Medicine at the FDA (Fig 1). ...
Citations
... 5 Both non-selective COX inhibitors and COX-2-selective inhibitors have been reported to be effective in providing postoperative analgesia in cats after orthopedic and soft tissue surgeries. [1][2][3]5,[8][9][10][11][12] In other studies, robenacoxib demonstrated superior analgesia when compared with placebo in cats undergoing onychectomy, 8 and provided effective analgesia similar to that provided by meloxicam for orthopedic surgery 9 and OVH. 3 Although NSAIDs are efficacious in providing analgesia for postoperative pain, there is concern about GI and renal adverse effects, which have been reported in cats. 13 These adverse effects are due to the inhibition of the constitutive functions of COX enzymes and the subsequent alteration of production of PGs involved in the maintenance of tissues. ...
... 6 Grapiprant is an antagonist at the PGE 2 prostanoid receptor, EP4. 11,12,15 EP4 receptors are localized in the dorsal root ganglion of the spinal cord and peripheral nociceptors, and are associated with mediation of inflammatory pain. [16][17][18][19] Due to the selectivity of grapiprant at this receptor, the production of prostanoids and thus homeostatic functions are preserved. ...
... 12 Currently, grapiprant is licensed for and has been shown to be efficacious in attenuating canine osteoarthritis with a published oral dose of 2 mg/kg every 24 h. 11 Ross et al 20 showed that grapiprant was efficacious in attenuating acute soft tissue pain associated with OVH. Therefore, safe alternatives to traditional NSAIDs to broaden the spectrum of treatments for acute feline pain are desired. ...
Objectives
The main objective of this study was to compare the postoperative analgesic effects of grapiprant with those of robenacoxib in cats undergoing ovariohysterectomy (OVH).
Methods
In total, 37 female cats (age range 4 months–10 years, weighing ⩾2.5 kg) were enrolled in a prospective, randomized, masked, non-inferiority (NI) clinical trial. Cats received oral robenacoxib (1 mg/kg) or grapiprant (2 mg/kg) 2 h before OVH. Analgesia was assessed via the Feline Grimace Scale (FGS), the Glasgow Composite Measure Pain Scale-Feline (CMPS-F), von Frey monofilaments (vFFs) and pressure algometry (ALG) 2 h before treatment administration, at extubation, and 2, 4, 6, 8, 18 and 24 hours after extubation. Hydromorphone (<8 h postoperatively) or buprenorphine (>18 h postoperatively) were administered to cats with scores of ⩾5/20 on CMPS-F and/or ⩾4/10 on FGS. NI margins for CMPS-F and vFFs were set at 3 and −0.2, respectively. A mixed-effect ANOVA was used for FGS scores ( P <0.05). Data are reported as mean ± SEM.
Results
The data from 33 cats were analyzed. The upper limit of the 95% confidence interval (CI) (0.35) was less than the NI margin of 3 for CMPS-F, and the lower limit of the 95% CI (0.055) was greater than the NI margin of −0.2 for vFFs, indicating NI of grapiprant. The FGS scores were greater than baseline at extubation for both treatments (1.65 ± 0.63; P = 0.001); however, there was no difference between treatments. There was no difference between treatments, nor treatment by time interaction, for vFFs ( P <0.001). The CMPS-F scores for both treatments were higher at extubation but returned to baseline after 4 h ( P <0.001). For ALG, there was no difference in treatment or treatment by time interaction. The robenacoxib group had lower pressure readings at extubation and 6 h compared with baseline.
Conclusions and relevance
These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown.
... This selective EP4 inhibition allows for other PGs to remain active, which may theoretically offer an improved safety profile. In dogs, grapiprant has been reported to decrease lameness due to OA (Rausch-Derra, Huebner, et al., 2016) and was effective in decreasing postoperative pain associated with ovariohysterectomy (Ross et al., 2022). Given the evidence for efficacy in both chronic orthopedic pain and acute, soft tissue pain in dogs, grapiprant is anticipated to be a useful analgesic for a wide variety of noxious processes in pigs. ...
... This dose was chosen based on results of a previous pilot study in 2 pigs, which determined that a dose of 2 mg/kg resulted in insufficient plasma concentrations in pigs compared to plasma concentrations determined to be efficacious in dogs (Nagahisa & Okumura, 2017). Assuming a linear increase in plasma concentrations, the dosage was increased to reach effective analgesic plasma concentrations based on those reported in dogs (Rausch-Derra, Huebner, et al., 2016;. Blood was collected at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h following the administration of grapiprant. ...
... The bioavailability of drugs from the gastrointestinal tract is affected by lipid solubility and dissolution of the drug, fat content of the diet, and hepatic firstpass metabolism (Homer et al., 2005). Given that previous studies evaluating the PK parameters of this formulation of grapiprant used fasted animals (Knych et al., 2018;Lebkowska-Wieruszewska, De Vito, et al., 2017;Rausch-Derra, Huebner, et al., 2016;, grapiprant was administered to fasted pigs to facilitate comparison between species. ...
Both pet and research pigs can suffer from some degree of pain from surgery, injuries, or osteoarthritis (OA). Despite this, there is a paucity of data on safe and effective analgesia agents in pigs. Grapiprant is an EP4 antagonist that blocks the action of the pro-inflammatory prostanoid, PGE2 . It has shown efficacy in attenuating pain associated with ovariohysterectomy and OA in dogs. However, there are no data regarding grapiprant in pigs. Therefore, the pharmacokinetic profile of orally administered grapiprant to juvenile pigs (Sus scrofa domestica) was evaluated in this study. Seven juvenile pigs received 12 mg/kg grapiprant orally. Blood was collected from an indwelling jugular catheter using the push-pull method at set timepoints up to 48 hours. Sample analysis was performed with high-performance liquid chromatography. Mean grapiprant plasma concentration was 164.3 ± 104.7 ng/mL which occurred at 0.8 ± 0.3 h. This study demonstrated that grapiprant concentrations consistent with analgesia in dogs were reached at this dosage in pigs. Further studies are needed to evaluate the efficacy of grapiprant in pigs.
... However, the CPE remains a factor that must be considered when using CROMs, particularly in open-label settings [32] and likely even more so if the treatment is invasive [33]. The authors recommend blinding and placebo control if CROMs are to be used as the primary measure and it is noteworthy that regulators have taken a similar view [34,35]. In human medicine, when blinding is not possible, it is recommended that PROMs collection should be combined with functional, imaging and biochemical biomarkers adding an element of objectivity [36]. ...
Client-reported outcomes measures (CROMs) have been previously validated for the evaluation of canine osteoarthritis. A published systematic review indicated that the 'Liverpool Osteoarthritis in Dogs' (LOAD) and the 'Canine Orthopedic Index' (COI) can be recommended for use in dogs with osteoarthritis; these CROMs have also been used in the context of measuring surgical outcomes of dogs with orthopaedic conditions. However, the minimal clinically-important differences (MCIDs) for these CROMs have not been investigated. Such estimates would be useful for investigators and regulators so that these CROMs can be used in clinical trials. Data from the RCVS Knowledge Canine Cruciate Registry were extracted, and baseline and 6 week follow-up data on dogs that had received surgery for cranial cruciate ligament rupture were used to make estimates of MCIDs using distribution-based and anchor-based methods. Data from 125 dogs were categorised based on the anchor question and LOAD and COI scores analysed accordingly. The four anchor-based methods provided a range of MCIDs for each CROM (1 to 8.8 for LOAD and 3.5 to 17.6 for COI). In the two different distribution-based methods, the MCIDs for LOAD ranged from 1.5 (effect size) to 2.4 (standard error of measurement) and the effect size method yielded a result of 2.2 for COI. The results showed that the value of the MCIDs depended on the method that was applied. Receiver operator characteristic curves provided areas under the curve (AUCs) greater than 0.7, which indicated that the cut-off point was acceptable; LOAD had the greater AUC at 0.867. In summary, the authors currently recommend a MCID of '4' for LOAD and '14' for COI although further work in other clinical contexts (such as osteoarthritis associated with chronic pain) is required to add confidence to these estimates. For the first time, we have provided estimates for MCIDs for these two CROMs which will facilitate sample size estimates in future clinical studies that use these CROMs as outcomes measures.
... However, no hematological safety concerns were observed regarding AAT-008 in in vivo safety and toxicity studies (data not shown). Similar safety evidence of a selective EP4 antagonist (grapiprant/Galliprant ® for animal health) was also demonstrated in field studies using dogs with disease (31). Recently, other EP4 antagonists have been developed (32,33). ...
Background:
Prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four receptors (EP1-4). We investigated the radiosensitizing effects of a newly developed antagonist of PGE2-EP4 (AAT-008) in mouse colon cancer cells in vivo and explored the mechanism using flow cytometry (FCM).
Methods:
CT26WT cells grown in Balb/c mice were used. AAT-008 at doses of 0, 3, 10, and 30 mg/kg/day was orally administered once or twice daily for up to 19 days. On day 3, the tumors were irradiated at 9 Gy in the radiotherapy (RT) group. Tumor sizes were measured every other day. For the first FCM series, AAT-008 (10 mg/kg/day) was administered from day 0 to 18 and RT (9 Gy) was given on day 3. The population of effector T cells (Teff), defined as CD45+CD8+CD69+, in the tumors was investigated on day 19. For the second FCM series, AAT-008 (30 mg/kg/day) was administered from day 0 to 12. The populations of Teff and regulatory T cells (Treg), and the ratio of Teff/Treg were investigated on day 13.
Results:
The growth delay effect of AAT-008 administered alone (3-30 mg/kg/day) appeared minimal. In the first growth delay experiment where AAT-008 was administered once daily, the combined effect of AAT-008 (30 mg/kg/day) and RT appeared additive. In the second growth delay experiment where AAT-008 was administered twice daily, the combined effect appeared additive at 3 and 10 mg/kg/day and supra-additive at 30 mg/kg/day. In the first FCM series, the mean Teff proportions in the tumors were 43% and 31% in the 10 mg + RT and 0 mg + RT groups, respectively. Notably, 67% Teff was observed in responsive mice in the 10 mg + RT group. In the second FCM series, the mean Treg proportion and Teff/Treg ratio in the 0 mg + RT and 30 mg + RT groups were 4.0% and 1.5%, respectively (P=0.04) and 10 and 22, respectively (P=0.04).
Conclusions:
AAT-008 potentially enhances the radiosensitivity of colon cancer cells, apparently by stimulating the immune system against the cancer cells.
... Moreover, the EP4 receptor mediates the PGE2elicited inflammation and sensitization of sensory neurons [27][28][29][30] , leading to the development of targeted therapies for the OA-induced inflammation and pain 31,32 . For example, the EP4 antagonist Grapiprant has been approved for treating OA pain in dogs [33][34][35] . However, the role of EP4 in cartilage homeostasis still remains elusive as several studies have reported contradictory evidence, using agonists or antagonists exclusively [21][22][23][24][25][26]31,36,37 . ...
Articular cartilage repair and regeneration is an unmet clinical need because of the poor self-regeneration capacity of the tissue. In this study, we found that the expression of prostaglandin E receptor 4 (PTGER4 or EP4) was largely increased in the injured articular cartilage in both humans and mice. In microfracture (MF) surgery-induced cartilage defect (CD) and destabilization of the medial meniscus (DMM) surgery-induced CD mouse models, cartilage-specific deletion of EP4 remarkably promoted tissue regeneration by enhancing chondrogenesis and cartilage anabolism, and suppressing cartilage catabolism and hypertrophy. Importantly, knocking out EP4 in cartilage enhanced stable mature articular cartilage formation instead of fibrocartilage, and reduced joint pain. In addition, we identified a novel selective EP4 antagonist HL-43 for promoting chondrocyte differentiation and anabolism with low toxicity and desirable bioavailability. HL-43 enhanced cartilage anabolism, suppressed catabolism, prevented fibrocartilage formation, and reduced joint pain in multiple pre-clinical animal models including the MF surgery-induced CD rat model, the DMM surgery-induced CD mouse model, and an aging-induced CD mouse model. Furthermore, HL-43 promoted chondrocyte differentiation and extracellular matrix (ECM) generation, and inhibited matrix degradation in human articular cartilage explants. At the molecular level, we found that HL-43/EP4 regulated cartilage anabolism through the cAMP/PKA/CREB/Sox9 signaling. Together, our findings demonstrate that EP4 can act as a promising therapeutic target for cartilage regeneration and the novel EP4 antagonist HL-43 has the clinical potential to be used for cartilage repair and regeneration.
... Grapiprant is an EP4 receptor antagonist approved in the US for treatment of chronic, inflammatory pain associated with osteoarthritis in dogs. 10 This medication belongs to the piprant class of drugs and is considered a novel NSAID due to its unique, highly selective mechanism of action. Through sole binding to the EP4 receptor, piprants allow for the COX-derived prostaglandins to be both produced and active at receptors other than EP4. ...
OBJECTIVE
To evaluate and compare postoperative analgesic effects of grapiprant and carprofen in dogs undergoing ovariohysterectomy.
ANIMALS
42 sexually intact female healthy dogs (< 35 kg and 0.5 to 7 years old) were enrolled.
PROCEDURES
In a masked, randomized, noninferiority clinical trial, dogs received either 2 mg/kg of grapiprant or 4.4 mg/kg of carprofen orally 2 hours prior to ovariohysterectomy. Postoperative pain was assessed using the Glasgow Composite Pain Scale–Short Form (GCPS-SF) at extubation and 2, 4, 6, 8, 18, and 24 hours postextubation and compared to baseline. After each pain scoring, mechanical nociceptive testing with von Frey monofilaments (vF) was performed to assess hyperalgesia. Hydromorphone (0.05 mg/kg, IM) was administered to any dog with a GCPS-SF of ≥ 5/24. The noninferiority limit (NI) for the GCPS-SF was Δ = 3. The NI for vF was Δ = –0.2. Following noninferiority, a mixed-effect ANOVA and post hoc comparisons were made with the Tukey correction method ( P < .05).
RESULTS
3 dogs required rescue analgesia and were excluded from statistical analysis. Of the remaining 39 dogs, the upper CI for GCPS-SF was below the NI of 3 and the lower CI for vF was greater than the NI of –0.2, indicating noninferiority of grapiprant as compared to carprofen. There was no difference between treatment ( P = .89) nor treatment by time ( P = .62) for GCPS-SF. There was no difference between groups at any time point or over time when vF were used.
CLINICAL RELEVANCE
Our study results support the use of grapiprant as an analgesic alternative to carprofen in dogs undergoing ovariohysterectomy.
... Previous research on grapiprant indicates its very high potential in the treatment of pain and inflammation. It has been considered safe from a long-term oral administration perspective and has proven to be a good alternative for pain relief in dogs with osteoarthritis (OA) compared to popular NSAIDs [18,19]. The analgesic effect of grapiprant has also been tested in phase II clinical trials in humans with OA. ...
Grapiprant is a new analgesic and anti-inflammatory drug belonging to the piprant class, approved in 2016 by the FDA Veterinary Medicine Center for the treatment of pain and inflammation associated with osteoarthritis in dogs. It acts as a highly selective antagonist of the EP4 receptor, one of the four prostaglandin E2 (PGE2) receptor subtypes. It has been shown to have anti-inflammatory effects in rat models of acute and chronic inflammation and clinical studies in people with osteoarthritis. The current state of knowledge suggests the possibility of using it in oncological therapy. The manuscript presents the development of conditions for the identification and quantitative determination of grapiprant by thin-layer chromatography with densitometric detection. The optimal separation of the substance occurs using silica gel 60F254 chromatographic plates and the mobile phase containing ethyl acetate-toluene-butylamine. Validation (according to ICH requirements) showed that the developed method is characterized by straightness of results in a wide concentration range with the limit of detection of 146.65 µg/mL. The %RSD values of the precision and accuracy confirm the sensitivity and reliability of the developed procedure. Next, the method was used for quantification of grapiprant in a pharmaceutical preparation, and for stability studies under various environmental conditions. Additionally, the mass studies were carried out on the stressed samples using the UPLC-MS/MS method. The degradation products were primarily characterized by comparing their mass fragmentation profiles with those of the drug. The results indicated a potential degradation pathway for grapiprant.
... The management of OA in dogs is a lifetime commitment, involving a multimodal approach based on relieving the symptoms of the disease by treating pain and inflammation, improving mobility and hence quality of life, whilst protecting joints from OA [11][12][13][14][15]. Non-steroidal anti-inflammatory drugs (NSAIDs) have been the medical cornerstone for the management of pain and inflammation in canine OA for many years [16,17] and preferential and selective cyclooxygenase-2 (COX-2) inhibitors have been developed to potentially reduce the risk of unwanted side effects caused by the inhibition of COX-1 [18,19]. Further to classic NSAIDs therapy, newly registered products such as grapiprant and bedinvetmab have also shown efficacy in the control of pain associated to OA [20,21]. ...
... The finding that both products showed clear superiority to the placebo group in both assessments assures the presence of the disease in the study population and strengthens the efficacy of both products and the non-inferiority conclusion [52]. The inclusion of a placebo group also allows the detection of an important placebo effect, as repeatedly described for this type of studies [20,[53][54][55][56], which is observed in both the veterinary and the owner assessments. ...
... However, there is an element of inherent subjectivity which has been limited by keeping the owners also blinded to treatment to avoid any bias and by using this validated tool [44,45]. Likewise, the treatment success criteria was previously defined by Brown et al. [55,60] and has been recently used in the efficacy evaluation for the treatment of OA in similar studies with grapiprant [20] or bedinvetmab [21]. Interestingly, in this study, according to the owner's assessment, enflicoxib achieved a much higher treatment success (90.4%) compared to the above-mentioned studies (48.1% and 52.6% for grapiprant and bedinvetmab, respectively). ...
Background
This prospective, multisite, blinded, randomized, non-inferiority clinical study aimed to confirm the efficacy and safety of enflicoxib in the treatment of pain and inflammation associated with canine osteoarthritis. A total of 180 dogs were randomized to receive enflicoxib (n = 78), mavacoxib (n = 80) or placebo (n = 22). Dogs underwent veterinary assessments from day 0 to day 42 using a clinical sum score (CSS). Efficacy was also assessed by the owners using the Canine Brief Pain Inventory (CBPI). The primary efficacy endpoint was the overall CSS from day 0 to day 42.
Results
The overall CSS expressed as area under the curve demonstrated non-inferiority of enflicoxib compared to mavacoxib, and both showed superiority over placebo. At the end of the study, average CSS, and the percentage of CSS responders for enflicoxib (3.64 and 74%) and mavacoxib (4.49 and 68%), was superior to placebo (7.15 and 29%). A faster onset of action was observed for enflicoxib as superiority over placebo was evidenced from the first efficacy assessment (day 7) onwards for both parameters, whereas mavacoxib was only significantly different from day 14 onwards. According to the owner assessment, the percentage of CBPI responders was 90%, 79%, and 43% for dogs treated with enflicoxib, mavacoxib and placebo, respectively, and superiority over placebo was demonstrated for both active treatments. In all secondary parameters, non-inferiority of enflicoxib versus mavacoxib was confirmed. The dog’s quality of life improved in all groups, but only enflicoxib showed superiority versus placebo. When assessing severely affected dogs only, results were similar, thus confirming the efficacy of enflicoxib in all stages of canine OA. There were no differences between groups in the frequency of adverse events, which were most frequently mild affecting the gastrointestinal tract and recovered without treatment.
Conclusions
Enflicoxib is efficacious and safe for the treatment of pain and inflammation in any stage of canine osteoarthritis with a faster onset of action compared to mavacoxib.
... Grapiprant is currently FDA approved for the treatment of pain associated with canine osteoarthritis 8,9 ; however, the current literature 10,11 regarding ...
... This time point was chosen based on the pharmacokinetics of grapiprant, which would have an anticipated time to maximum plasma concentrations between 1 and 2 hours postadministration. 9 Similarly, maximum plasma concentrations are achieved in 1 to 3 hours after oral administration of carprofen. 16 Dogs were then moved to the surgery preparatory room. ...
OBJECTIVE
To compare the analgesic efficacy of grapiprant to carprofen for the treatment of postoperative pain and inflammation in dogs following ovariohysterectomy.
ANIMALS
12 purpose-bred adult sexually intact female Beagles.
PROCEDURES
Dogs were randomly assigned to 1 of 2 treatment groups: grapiprant (2 mg/kg, PO; n = 6) or carprofen (4.4 mg/kg, PO; n = 6), 1.5 hours prior to ovariohysterectomy (OVH) and every 24 hours afterward for 3 total doses. An ultrafiltration probe was placed within the OVH incision to collect interstitial fluid (ISF). Pain and inflammation were assessed by masked investigators via mechanical nociceptive threshold testing and the short form of the Glasgow Composite Pain Scale before drug administration and at multiple time points for 72 hours following dosing and surgery. ISF samples were collected at the same time points to assess prostaglandin E 2 concentrations at the site of inflammation.
RESULTS
In both groups, pain scale scores were highest in the immediate postoperative period and decreased over time. In both treatment groups, there were significant ( P = 0.003) differences in mechanical nociceptive threshold results over time when compared with baseline, but there was no difference between groups. Prostaglandin E 2 concentrations in ISF were higher in dogs receiving grapiprant compared with carprofen ( P < 0.001). One dog in the carprofen group required rescue analgesia.
CLINICAL RELEVANCE
Results of this preliminary study suggested both carprofen and grapiprant may be effective for postoperative pain following OVH in dogs; however, additional studies are warranted to determine grapiprant’s effectiveness in a larger and more diverse population of dogs.
... RTHAs achieved plasma concentrations much higher than the canine minimum effective concentration (MEC) of 164 ng/mL. 9,[11][12][13] To the authors' knowledge, the previous report was the first and only study to evaluate grapiprant in any avian species. 13 The oral bioavailability of grapiprant is affected by food intake in mammals. ...
... The canine grapiprant MEC of 164 ng/mL was used. 9,14,[17][18][19] Results Animals All 6 RTHAs were healthy and completed the single dose with food administration as planned with no changes in urofeces or mentation. Mean body weight was 1.06 kg (range, 0.93 to 1.22 kg) at T0 for this study. ...
OBJECTIVE
Describe the pharmacokinetics of grapiprant administered orally with food to red-tailed hawks (RTHAs; Buteo jamaicensis ) and compare the results with previously described grapiprant pharmacokinetics administered without food in this species.
ANIMALS
6 healthy adult RTHA (3 males, 3 females) under human care.
PROCEDURES
A single dose of grapiprant (30 mg/kg) was given orally to RTHAs, followed by force-feeding. Blood samples were obtained at 14 time points for 120 hours postgrapiprant administration. Plasma concentrations of grapiprant were measured via tandem liquid chromatography-mass spectrometry. Nonparametric superimposition using pharmacokinetic modeling software used plasma concentrations to calculate simulations of grapiprant plasma concentrations for 30 mg/kg administered orally with food every 12 hours.
RESULTS
The arithmetic mean maximum plasma concentration was 405.8 ng/mL, time to maximum plasma concentration was 16 hours, and harmonic mean terminal half-life was 15.6 hours. Simulations determined 30 mg/kg every 12 hours could attain minimum effective concentrations (> 164 ng/mL) reported in dogs for a sustained period of approximately 20 hours.
CLINICAL RELEVANCE
Grapiprant plasma concentrations were achieved above the canine therapeutic concentrations within 16 hours postmedication. Mean concentrations were maintained for approximately 20 hours. Simulations support a dosing frequency of 12-hour intervals with food reaching minimum effective concentrations established for canines, although it is unknown whether these plasma concentrations are therapeutic for birds. Bioaccumulation was not noted on simulations secondary to increased grapiprant administration. Further research including multidose assessments at this current dose with food, in vitro pharmacological characterization, and pharmacodynamic studies in this species are warranted.
