Pharmacokinetics of grapiprant administered to red-tailed hawks (Buteo jamaicensis) after food was withheld for 24 hours

Paula Rodriguez From the William R. Pritchard Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, and K. L. Maddy Equine Analytical Pharma-cology Laboratory, School of Veterinary Medi-cine, University of California-Davis, Davis, California.

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Joanne R. Paul-Murphy From the William R. Pritchard Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, and K. L. Maddy Equine Analytical Pharma-cology Laboratory, School of Veterinary Medi-cine, University of California-Davis, Davis, California.

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Heather K. Knych From the William R. Pritchard Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, and K. L. Maddy Equine Analytical Pharma-cology Laboratory, School of Veterinary Medi-cine, University of California-Davis, Davis, California.

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Tracy L. Drazenovich From the William R. Pritchard Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, and K. L. Maddy Equine Analytical Pharma-cology Laboratory, School of Veterinary Medi-cine, University of California-Davis, Davis, California.

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Michelle G. Hawkins From the William R. Pritchard Veterinary Medical Teaching Hospital, Department of Medicine and Epidemiology, and K. L. Maddy Equine Analytical Pharma-cology Laboratory, School of Veterinary Medi-cine, University of California-Davis, Davis, California.

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Abstract

OBJECTIVE

To identify an oral dose of grapiprant for red-tailed hawks (RTHAs; Buteo jamaicensis) that would achieve a plasma concentration > 164 ng/mL, which is considered therapeutic for dogs with osteoarthritis.

ANIMALS

6 healthy adult RTHAs.

PROCEDURES

A preliminary study, in which grapiprant (4 mg/kg [n = 2], 11 mg/kg [2], or 45 mg/kg [2]) was delivered into the crop of RTHAs from which food had been withheld for 24 hours, was performed to obtained pharmacokinetic data for use with modeling software to simulate results for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg. Simulation results directed our selection of the grapiprant dose administered to the RTHAs in a single-dose study. Plasma grapiprant concentration, body weight, and gastrointestinal signs of RTHAs were monitored.

RESULTS

On the basis of results from the preliminary study and simulations, a grapiprant dose of 30 mg/kg was used in the single-dose study. The geometric mean maximum observed plasma concentration of grapiprant was 3,184 ng/mL, time to maximum plasma grapiprant concentration was 2.0 hours, and the harmonic mean terminal half-life was 17.1 hours. No substantial adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Although the single dose of grapiprant (30 mg/kg) delivered into the crop achieved plasma concentrations > 164 ng/mL in the RTHAs, it was unknown whether this concentration would be therapeutic for birds. Further research that incorporates multidose assessments, safety monitoring, and pharmacodynamic data collection is warranted on the use of grapiprant in RTHAs from which food was withheld versus not withheld.

Abstract

OBJECTIVE

To identify an oral dose of grapiprant for red-tailed hawks (RTHAs; Buteo jamaicensis) that would achieve a plasma concentration > 164 ng/mL, which is considered therapeutic for dogs with osteoarthritis.

ANIMALS

6 healthy adult RTHAs.

PROCEDURES

A preliminary study, in which grapiprant (4 mg/kg [n = 2], 11 mg/kg [2], or 45 mg/kg [2]) was delivered into the crop of RTHAs from which food had been withheld for 24 hours, was performed to obtained pharmacokinetic data for use with modeling software to simulate results for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg. Simulation results directed our selection of the grapiprant dose administered to the RTHAs in a single-dose study. Plasma grapiprant concentration, body weight, and gastrointestinal signs of RTHAs were monitored.

RESULTS

On the basis of results from the preliminary study and simulations, a grapiprant dose of 30 mg/kg was used in the single-dose study. The geometric mean maximum observed plasma concentration of grapiprant was 3,184 ng/mL, time to maximum plasma grapiprant concentration was 2.0 hours, and the harmonic mean terminal half-life was 17.1 hours. No substantial adverse effects were observed.

CONCLUSIONS AND CLINICAL RELEVANCE

Although the single dose of grapiprant (30 mg/kg) delivered into the crop achieved plasma concentrations > 164 ng/mL in the RTHAs, it was unknown whether this concentration would be therapeutic for birds. Further research that incorporates multidose assessments, safety monitoring, and pharmacodynamic data collection is warranted on the use of grapiprant in RTHAs from which food was withheld versus not withheld.

Introduction

Red-tailed hawks (RTHAs; Buteo jamaicensis) are one of the most widespread and common hawks of North America. These hawks are commonly used in falconry and are also presented to wildlife rehabilitation centers with medical and surgical issues such as trauma, toxicosis, and infectious diseases.1,2 A retrospective study2 of causes of morbidity and mortality of free-living raptors admitted to a veterinary teaching hospital shows that 66.3% (271/409) of the raptors were presented with evidence of trauma. When injuries are severe enough to deem raptors nonreleasable to the wild, individual birds are sometimes managed as species ambassadors at educational centers and zoos. Captive raptors have long life spans, partially because of the veterinary care provided to them.3 One of the most common diseases in captive RTHAs is osteoarthritis. Birds used in falconry often develop osteoarthritis of the shoulder, elbow, carpus, stifle, and tarsal joints.3 To our knowledge, there has not been a retrospective report on the incidence of osteoarthritis in falconry hawks or hawks in educational institutions; however, a retrospective study2 of free-living raptors that had been presented to a veterinary teaching hospital shows that only 0.5% (2/409) had degenerative disease. Osteoarthritis is a complex response of joint tissue to aging, trauma, genetics, and environmental factors leading to alteration of articular cartilage and subchondral bone homeostasis.4 There are 2 major categories of underlying causes of osteoarthritis: abnormal stress on a joint from developmental abnormalities, obesity, fractures, trauma, loss of joint stability, abnormal cartilage in a joint from genetic or metabolic disease, aging, inflammation, and immune response. In captive hawks, the main reasons suspected for osteoarthritis are previous trauma and aging.3

Nonsteroidal anti-inflammatory drugs are the most common treatment for inflammation and musculoskeletal pain in many species, including birds, and these drugs exert therapeutic effects by inhibition of cyclooxygenase (COX)‐1 and COX‐2 pathways, thereby blocking the conversion of arachidonic acid to proinflammatory prostaglandin mediators.5,6 The inhibition of COX enzymes also inhibits other mediators responsible for functions associated with cellular homeostasis, leading to potential adverse effects, including renal, gastrointestinal, and hemostatic adverse effects.5,6,7 Common NSAIDs used in avian medicine include meloxicam, carprofen, ketoprofen, celecoxib, and piroxicam, each with a distinct COX-1–to–COX-2 ratio and differing reports of effectiveness and toxicosis in birds.6,7,8

Meloxicam is a COX-2–selective NSAID and has become the most widely used anti-inflammatory medication in avian practice.7,8 A recent study9 of American kestrels (Falco sparverius) to which high-dose meloxicam (20 mg/kg, PO, q 12 h for 7 days) was administered shows that a few birds developed gastric ulcers, but nephrotoxicity was not detected on biochemical analyses or histologic examination of the kidneys. Direct toxicosis owing to reactive oxygen species and interference with uric acid transport has been observed in Gyps vultures exposed to diclofenac, carprofen, flunixin, ibuprofen, and phenylbutazone.10,11,12 Adverse effects of NSAIDs in raptor species need further investigation.

Grapiprant, an NSAID that is classified as a prostaglandin E2 receptor antagonist that does not inhibit COX enzymes, was recently approved for use in dogs.13,14,15 Grapiprant binds to prostaglandin E2 receptor 4 (EP4) receptors, blocking the sensitization of sensory neurons and stimulation of inflammation mediated by prostaglandin E2.15 Throughout the body, EP receptor are involved in multiple physiologic and pathophysiologic processes, including contributing to proinflammatory actions.16,17 For instance, in dogs, EP4s are the primary mediator of osteoarthritis pain and inflammation and are found in various tissues and cells, including those of the immune, osteoarticular, cardiovascular, gastrointestinal, and respiratory systems and cancer cells.17 Grapiprant is reported15,18,19 to be an effective treatment for alleviating signs of pain in dogs with osteoarthritis and appears to be tolerated well following oral administration of 2 mg/kg daily for 28 days.15,18,19 Grapiprant is also reported to be tolerated well in cats,16 rabbits,20 and horses.21 Studies14,20,22 of mice and rats show that grapiprant can suppress and modulate acute and chronic pain and inflammation. Although there is conflicting evidence that shows carprofen and firocoxib are more effective than grapiprant for treating acute joint pain in dogs,23,24 results of a prospective study15 indicate the effectiveness of grapiprant in managing osteoarthritis in dogs.15 However, grapiprant did not alleviate signs of pain and lameness in dogs in models for acute joint inflammation experimentally induced with an IA injection of a sodium urate crystal suspension to induce either acute synovitis23 or acute arthritis.24

To our knowledge, no reports describe the use of grapiprant in any avian species. The unique mechanism of action of grapiprant may offer a more targeted and presumedly better treatment of acute and chronic inflammation and pain management in birds with less adverse effects than other treatments. The purpose of the study reported here was to identify a grapiprant dose that, when given orally to RTHAs from which food had been withheld for 24 hours, achieved plasma grapiprant concentrations > 164 ng/mL, which is considered therapeutic for dogs with osteoarthritis. We hypothesized that grapiprant, at the doses administered, would have minimal adverse effects in RTHAs.

Materials and Methods

Animals

The RTHAs eligible for the study were 6 RTHAs that were permanent residents of the California Raptor Center at the University of California-Davis School of Veterinary Medicine because they were deemed nonreleasable due to previous injuries or visual deficits. For inclusion, the RTHAs had to have been healthy on the basis of results of a physical examination and hematologic and serum biochemical analyses and must not have received any medications, including anesthetics, for ≥ 2 years prior. Red-tailed hawks were not excluded if they had been vaccinated against West Nile virus within the previous 2 years.

Housing and feeding—For the preliminary study and the first 48 hours of the single-dose study, RTHAs were individually housed in stainless steel hospital cages (61.5 cm wide × 72.05 cm high × 70.5 cm deep) in 1 room, and cage fronts were covered with newspaper to reduce stress from human activities in the room. The light cycle was 12 to 14 hours of light and 10 to 12 hours of darkness. The RTHAs were returned to their permanent outdoor enclosures after the phlebotomy at the 48-hour time point.

Water was provided ad libitum, and the RTHAs’ daily diet was based on their resting energy requirement and consisted of killed mice and day-old chicks. During the study, force-feeding was implemented if a RTHA had no signs of appetite 24 hours after receiving grapiprant.

Monitoring for adverse effects—The RTHAs were monitored for regurgitation and signs of mentation changes or decreased appetite. The presence and characteristics of urofeces were monitored daily for obvious diarrhea, melena, hemorrhage, or bright green appearance. Body weights were also monitored daily.

Study protocols

We conducted a preliminary study of various doses of grapiprant to gather data for use in determining the dose of grapiprant later used in single-dose study. All study procedures were approved by the Institutional Animal Care and Use Committee of the University of California (No. 21492).

Preliminary study—The 6 RTHAs were randomly25 assigned to receive 1 of 3 doses of grapiprant: 4 mg/kg (n = 2), 11 mg/kg (2), or 45 mg/kg (2). Our 2 lower doses were calculated on the basis of metabolic scaling26,27,28,29 to adjust the 2 lowest doses (1 and 6 mg/kg) used in a study18 of dogs. Our highest dose (similar to the high dose of 50 mg/kg administered to dogs in that same study18) was determined by applying the same scaling calculations to a grapiprant dose of 25 mg/kg (Appendix 1).26,27,28,29,30 A previous study31 in dogs shows nonlinear (saturation) kinetics and changes in volume distribution and clearance with changes in dose, which presented challenges when metabolic scaling was performed. Because, to our knowledge, there were no pharmacokinetic data for the use of grapiprant in any bird species, we selected 164 ng/mL as the target plasma concentration of grapiprant for the RTHAs on the basis of therapeutic plasma concentrations in dogs.16,19,32

Because absorption of the drug could be greater for animals from which food has been withheld versus not withheld,21,31 our study design included withholding food from the RTHAs for 24 hours before treatment with grapiprant. Water was available ad libitum, and the 24 hours of food withholding coincided with the RTHAs’ regularly scheduled weekly day that food was withheld. Food was next offered 6 hours following phlebotomy at the 6-hour time point after grapiprant administration.

For phlebotomy, birds were restrained manually and their heads were covered with a cloth hood. Blood was collected just before grapiprant administration (time 0) and at 14 time points (0, 5, 10, 15, and 30 minutes and 1, 2, 4, 6, 10, 16, 20, 24, and 72 hours) after grapiprant administration. Because the initial collection time points were in close succession, each RTHA was restrained and hooded for the first 30 minutes to minimize stress from repeated capture. The amount of blood collected at any time point was ≤ 1% of each RTHA’s body weight. For each phlebotomy, 0.4 mL of blood was collected from the metatarsal, cutaneous ulnar, or jugular vein with a 26- or 27-gauge needle attached to a 1-mL tuberculin syringe. The blood was immediately transferred to pediatric collection tubes containing lithium heparin (Microtainer; Becton, Dickinson and Co), then stored on ice for a maximum of 3 hours until centrifugation for 10 minutes at 3,500 × g. The plasma was then separated, placed in labeled 0.5-mL cryotubes (Bio Plas Inc), and stored at –70 °C until analysis.

For each treatment, grapiprant 20-mg tablets (Galliprant) were crushed to a fine powder with a mortar and pestle, then the appropriate dose for each RTHA was measured with a digital analytic balance precision scale and placed into size-3 or size-4 gelatin capsules (Medisca). Each RTHA was manually restrained, and oral administration was completed by digitally placing the capsule into the crop and massaging it past the thoracic inlet. This was immediately followed by the administration of 10 mL of water through a 14F red rubber catheter inserted oropharyngeally and advanced into the crop. Pharmacokinetic results for subsequent plasma grapiprant concentrations were then used to perform a nonparametric superimposition with pharmacokinetic modeling software (Phoenix WinNonlin version 8.0; Certara) to simulate results for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg.

Single-dose study

Results of the preliminary study directed the selection of the grapiprant dose for administration to the same 6 RTHAs after a 6-week washout period. The single-dose study followed the same protocol, except that all birds received the same dose and blood samples were obtained at 14 time points for 120 hours (0, 10, 15, and 30 minutes and 1, 2, 4, 6, 10, 16, 24, 48, 96, and 120 hours) after grapiprant administration.

Determining grapiprant concentrations and pharmacokinetic results

Plasma calibrators were prepared with the use of certified reference standards for grapiprant (Cayman Chemical Co). Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, grapiprant quality control samples (RTHA plasma fortified with grapiprant at 3 concentrations [0.3, 10, and 500 ng/mL] within the standard curve) were prepared in replicates (n = 6), included with each sample set, and analyzed to determine the precision and accuracy of the assay. Samples were extracted, and grapiprant concentrations were determined with liquid chromatography–tandem mass spectrometry as previously described.21 Pharmacokinetic analysis was performed on plasma grapiprant concentrations by the use of noncompartmental analysis with a commercially available software program (Phoenix WinNonlin version 8.0; Certara). The maximum observed concentration (Cmax), time to maximum concentration (tmax), and duration of time that plasma concentrations were maintained above 164 ng/mL were based on visual inspection of the concentration-time data.16,19,31 Results for log-transformed terminal slope of the concentration-versus-time curve (λz) were used to calculate the terminal half-life (t1/2λ) with the following formula: t1/2λ = 0.693/λz. The area under the concentration-versus-time curve from time 0 to infinity (AUC0–∞) was determined with the use of standard pharmacokinetic equations (Phoenix WinNonlin version 8.0; Certara).

Results

Animals

All 6 RTHAs (3 males and 3 females) were healthy and completed the preliminary and single-dose studies as planned. Their estimated ages ranged from 6 to 18 years. Median body weight was 1.29 kg (range, 1.14 to 1.64 kg) at T0 for the preliminary study and 1.25 kg (range, 1.10 to 1.43 kg) at T0 for the single-dose study.

Assay characteristics

The concentration-response relationship (relationship between calibrators and the liquid chromatography–tandem mass spectrometry instrument response) was linear (r = 0.99). Accuracy of the assay for plasma concentration of grapiprant was 105%, 105%, or 98% for the quality control samples of RTHA plasma containing plasma grapiprant concentration of 0.3, 10, or 500 ng/mL, respectively. The precision of the assay was 9%, 4%, and 4% for 0.3, 10, and 500 ng/mL, respectively. The limit of quantitation was the lowest calibrator that could be measured with acceptable precision (back-calculated concentration not exceeding 20% of the CV) and accuracy (within 20% of the nominal concentration), and the limit of detection was established based on the lowest calibrator with a 3:1 signal-to-noise ratio. The technique was optimized to provide a limit of quantitation of 0.1 ng/mL and a limit of detection of approximately 0.05 ng/mL for grapiprant.

Preliminary study

Neither grapiprant dose of 4 mg/kg nor 11 mg/kg resulted in RTHA plasma grapiprant concentrations > 164 ng/mL (the target plasma grapiprant concentration) for the 24-hour duration desired; however, 1 RTHA treated with grapiprant dosed at 4 mg/kg and 1 dosed at 11 mg/kg had plasma grapiprant concentrations > 164 ng/mL at a single time point (the 20-hour and 2-hour time points, respectively). Both RTHAs treated with grapiprant dosed at 45 mg/kg had plasma grapiprant concentrations that exceeded the target plasma concentration at 4 hours and striking differences in the Cmax (562.8 and 3,603.5 ng/mL), indicating intraspecies variation. Overall, the mean ± SD t1/2 was 7.96 ± 1.26 hours (range, 6.41 to 10.2 hours) and was similar across treatment groups. The half-life for drug elimination (t1/2ke) of grapiprant was estimated to have been 7.5 hours.

With pharmacokinetic data from the preliminary study, plasma concentration simulations were performed for grapiprant doses of 20, 25, 30, 35, and 40 mg/kg (Figure 1). The simulated grapiprant dose of 30 mg/kg was selected for the single-dose study because results indicated that the dose was the lowest that would yield plasma grapiprant concentrations > 164 ng/mL by 2 hours after administration and maintain plasma grapiprant concentrations above this target concentration for up to 24 hours (Figure 1), with a t1/2ke of 70 to 80 hours (99.9% for 10 t1/2ke).

Figure 1
Figure 1

Results of simulations for log-transformed plasma grapiprant concentrations for 1 dose of 20, 25, 30, 35, or 40 mg of grapiprant/kg on the basis of data gathered during a preliminary study in which 6 healthy adult red-tailed hawks (RTHAs; Buteo jamaicensis) were randomly assigned to receive 1 of 3 doses of grapiprant: 4 mg/kg (n = 2), 11 mg/kg (2), or 45 mg/kg (2) after food was withheld for 24 hours.

Citation: American Journal of Veterinary Research 82, 11; 10.2460/ajvr.82.11.912

Single-dose study

Each of the 6 RTHAs received 30 mg of grapiprant/kg, prepared and administered orally into the crop as described earlier. At 2 hours after administration, the plasma concentration of grapiprant exceeded the target concentration of 164 ng/mL in all 6 RTHAs, and the mean ± SD plasma grapiprant concentration at 24 hours after administration was 205.3 ± 287.7 ng/mL (Figure 2). The overall mean ± SD t1/2 was 21.9 ± 20.6 hours (range, 9.6 to 63.3 hours). Results for the λz, t1/2λ, tmax, Cmax, area under the concentration-versus-time curve from time 0 to the last measured concentration (AUC0–last), and AUC0–∞ were compiled (Table 1).

Figure 2
Figure 2

Log-transformed plasma grapiprant concentration measurements following administration of a single dose of grapiprant (30 mg/kg, PO) at time 0 into the crop of 6 healthy RTHAs from which food had been withheld for 24 hours before treatment. The solid blue line represents the mean ± SD plasma grapiprant concentrations of all 6 RTHAs. The dashed horizontal line represents the plasma grapiprant concentration of 164 ng/mL, which is considered therapeutic in dogs with osteoarthritis.

Citation: American Journal of Veterinary Research 82, 11; 10.2460/ajvr.82.11.912

Table 1

Pharmacokinetic results for a single dose of grapiprant (30 mg/kg) administered PO and advanced into the crop of 6 healthy adult red-tailed hawks (RTHAs; Buteo jamaicensis).

Parameter Mean (range)
AUC0–last (h•ng/mL) 20,708 (11,313–39,544)
AUC0–∞ (h•ng/mL) 20,736 (11,317–39,556)
λz (h–1) 0.041 (0.011–0.072)
t1/2λ (h)* 17.1 (9.85–63.3)
Cmax (ng/mL) 3,184.2 (1,013.3–5,298.8)
tmax (h) 2.0 (2–6)

Data are reported as geometric mean and range, except where indicated.

AUC0–∞ = Area under the concentration-versus-time curve from time 0 to infinity. AUC0–last = Area under the concentration-versus-time curve from time 0 to the last measured concentration. Cmax = Maximum observed concentration. λz = Terminal slope of the concentration-versus-time curve. t1/2λ = Terminal half-life. tmax = Time to maximum concentration.

The harmonic mean and range are reported.

The median and range are reported.

Adverse effects

In both the preliminary and single-dose studies, minimal adverse effects were observed in the RTHAs. During the preliminary study, small amounts of regurgitated food were found at the bottom of the cages of the 2 RTHAs that received the highest dose of grapiprant (45 mg/kg). For these 2 birds, regurgitation was noticed for one at 20 hours after treatment when its plasma concentration of grapiprant was 3,603.3 ng/mL and for the other one at 72 hours after treatment, when its plasma concentration of grapiprant was 1.74 ng/mL. During the single-dose study (grapiprant, 30 mg/kg), no regurgitation was observed. The presence and characteristics of the urofeces of each RTHA were unchanged during both studies. Also, the birds remained bright, alert, and responsive at all times evaluated during both studies.

For the preliminary study, food consumption was reduced over the course of the study, with no birds eating the complete meal while in the hospital cages. For the single-dose study, 5 RTHAs had decreased food consumption during the initial 48 hours and were therefore force-fed once daily. Signs of inappetence in all affected RTHAs resolved after the birds were returned to outdoor enclosures at 48 hours. Five RTHAs lost body weight (range, 1.6% [0.02 kg/1.24 kg] to 24.7% [0.36 kg/1.454 kg]) during the first 48 hours of the single-dose study while maintained in indoor cages, whereas the remaining RTHA gained weight (Supplementary Table S1). Five of the 6 RTHAs weighed more at the 120-hour time point, compared with the 48-hour time point.

Discussion

Results of the present study indicate that when healthy RTHAs from which food had been withheld for 24 hours were treated with grapiprant (30 mg/kg, PO, and advanced to the crop), plasma grapiprant concentrations > 164 ng/mL (the plasma grapiprant concentration considered therapeutic in dogs with osteoarthritis)16,19,32 were maintained ≥ 24 hours without substantial adverse effects. Although plasma grapiprant concentrations > 164 ng/mL were achieved, we acknowledge that no pharmacodynamic data are available to support whether such plasma concentrations are therapeutic for birds. Because, to our knowledge, no previous reports describe the use of grapiprant in any avian species, we looked to studies of grapiprant pharmacokinetics in mammals, such as horses,21 cats,16 and dogs,31 and recognize that results show a range of species variability. The target plasma grapiprant concentration we selected for the RTHAs was based on findings from a pharmacodynamic clinical trial15 that included a multisite, masked, placebo-controlled, randomized field trial for the treatment of pain and inflammation of osteoarthritis in client-owned dogs. Our findings indicated that the geometric mean plasma grapiprant Cmax was higher for the RTHAs of the present study (3,184.2 ng/mL) than various means and ranges of concentrations reported in mammalian studies16,21,31; however, the dose we administered to the RTHAs was higher. Additionally, the median tmax of 2 hours for the RTHAs with food withheld for 24 hours was shorter than findings for dogs without food withheld (3 hours)31 but longer than findings for cats with food withheld (1.3 hours)16 and horses without food withheld (1.5 hours).21

The preliminary study was necessary to evaluate doses of grapiprant used in mammalian species that range from 2 to 50 mg/kg,15,16,18,20,21 and our selected doses were based on a study18 evaluating the safety of different doses administered to healthy dogs for 28 days combined with the fact that grapiprant had been approved for use in dogs. Because of the lack of pharmacokinetic data or prior experience with the use of grapiprant in avian species, metabolic scaling was used to extrapolate the doses26,27,28,29,30 evaluated in dogs to those for use in the RTHAs of the present study. Although controversial, metabolic scaling has been used to extrapolate doses across species on the basis of body weight and metabolic rate for other drugs not used in novel species.26,27 Metabolic scaling of drug doses has limitations owing to species differences in protein binding and routes and rates of elimination of a drug; however, the assumption of metabolic scaling is acceptable for preliminary studies to initiate drug testing in a new species.28,29,33 During our preliminary study, we also detected intraspecies variation, in that 1 of the 2 RTHAs treated with grapiprant dosed at 4 mg/kg and 1 of the 2 RTHAs dosed at 11 mg/kg had plasma grapiprant concentrations > 164 ng/mL at a single time point (the 20-hour and 2-hour time points, respectively). Further, both RTHAs treated with grapiprant dosed at 45 mg/kg had striking differences in their plasma grapiprant Cmax (562.8 and 3,603.5 ng/mL).

The RTHAs of the present study had food withheld for 24 hours before receiving grapiprant. We suspected that grapiprant administration with food would have lowered the plasma concentrations of the drug in the RTHAs, similar to findings in a study31 of 8 dogs that shows that the estimated bioavailability of the same oral dose of grapiprant (2 mg/kg) differed when administered to dogs that had food withheld (111.9%) versus not withheld (59.1%).

The most commonly reported clinical signs of adverse effects of grapiprant use in dogs and cats are emesis, soft feces, diarrhea, decreased appetite, and lethargy.15,18,34 We did not specifically evaluate drug safety in the present study; however, we monitored the RTHAs’ body weight, appetite, and urofeces and watched for clinical signs of gastrointestinal disturbances. Both RTHAs that received the highest dose of grapiprant (45 mg/kg) in the preliminary study regurgitated, however, the time of regurgitation (20 hours and 72 hours) and the corresponding grapiprant concentrations at those collection times (3,6305.5 ng/mL and 1.74 ng/mL respectively) varied widely. Although regurgitation could have been attributable to the high dose, it also could have been a result of the stress of having been handled for treatment and phlebotomy and having been maintained in smaller cages than their standard housing. In a grapiprant safety study18 of dogs, emesis and soft feces were noted in all treatment groups, including the control group, and were attributed to the stress of testing, kenneling, and restraint. No change in appetite or attitude was reported for dogs in that study.18 Food consumption was also less while the RTHAs were housed in the smaller indoor cages, compared with when returned to outdoor housing. A limitation was that birds were housed together in the outdoor enclosures, making it impossible to monitor how much each RTHA ate after having been transferred there from individual stainless steel cages. However, weight gain to higher-than-baseline body weight was an appropriate indicator of improved appetite. Thus, our findings supported our hypothesis that grapiprant at the doses administered would have minimal adverse effects in RTHAs. Future studies should consider the use of control animals to better determine whether changes in appetite are associated with the stress of handling and a new environment versus the effects of the administration of grapiprant.

Another limitation of the present study was the small sample size. The lowest number of RTHAs was used in the present study based on a previous study31 using a small sample size evaluating grapiprant; however, individual variability might be higher in a group of wild animals under human care, compared with a uniform population of laboratory animals used in research studies that may have very similar genetic lines. We also expected the SDs of data acquired to have been large because pharmacokinetic properties of drugs may have higher variability for oral administration than parenteral administration.35 Additionally, there is a lack of pharmacodynamic data in avian species to support the effectiveness of the target plasma grapiprant concentration used in the present study. Nonetheless, our results provided a foundation for future pharmacodynamic studies or clinical trials for the use of grapiprant in birds. Further research that incorporates multidose assessments, safety monitoring, and pharmacodynamic data collection is warranted on the use of grapiprant in RTHAs from which food was withheld versus not withheld.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org.

Acknowledgments

This study was funded by the Center for Companion Animal Health, School of Veterinary Medicine, University of California-Davis. The authors declare that there were no conflicts of interest.

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    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Naidoo V, Swan GE. Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction. Comp Biochem Physiol C Toxicol Pharmacol. 2009;149(3):269274.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Cuthbert R, Parry-Jones J, Green RE, et al. NSAIDs and scavenging birds: potential impacts beyond Asia’s critically endangered vultures. Biol Lett. 2007;3(1):9093.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Meteyer CU, Rideout BA, Gilbert M, et al. Pathology and proposed pathophysiology of diclofenac poisoning in free-living and experimentally exposed oriental white-backed vultures (Gyps bengalensis). J Wildl Dis. 2005;41(4):707716.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Giorgi M. CJ-023,423 (grapiprant) a potential novel active compound with antihyperalgetic properties for veterinary patients. Am J Anim Vet Sci. 2015;10:5356.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kirkby Shaw K, Rausch-Derra LC, Rhodes L. Grapiprant: an EP 4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Sci. 2015;2(1):39.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rausch-Derra L, Huebner M, Wofford J, et al. A prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP 4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med. 2016;30(3):756763.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Lebkowska-Wieruszewska B, De Vito V, Owen H, et al. Pharmacokinetics of grapiprant, a selective EP4 prostaglandin PGE2 receptor antagonist, after 2 mg/kg oral and i.v. administrations in cats. J Vet Pharmacol Ther. 2017;40(6):e11e15.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Yokoyama U, Iwatsubo K, Umemura M, et al. The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev. 2013;65(3):10101052.

  • 18.

    Rausch-Derra LC, Huebner M, Rhodes L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res. 2015;76(10):853859.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Rausch-Derra LC, Rhodes L, Freshwater L, et al. Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs. J Vet Pharmacol Ther. 2016;39(6):566571.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    De Vito V, Salvadori M, Poapolathep A, et al. Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan-induced inflammatory pain model in the rabbit. J Vet Pharmacol Ther. 2017;40(5):468475.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Knych HK, Seminoff K, McKemie DS. Detection and pharmacokinetics of grapiprant following oral administration to exercised Thoroughbred horses. Drug Test Anal. 2018;10:12371243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Nakao K, Murase A, Ohshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322(2):686694.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Budsberg SC, Kleine SA, Norton MM, et al. Comparison of two inhibitors of E-type prostanoid receptor four and carprofen in dogs with experimentally induced acute synovitis. Am J Vet Res. 2019;80(11):10011006.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    de Salazar Alcalá AG, Gioda L, Dehman A, et al. Assessment of the efficacy of firocoxib (Previcox) and grapiprant (Galliprant) in an induced model of acute arthritis in dogs. BMC Vet Res. 2019;15(1):309.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    True random number generator. Random.org. Accessed December 17, 2019. https://www.random.org

  • 26.

    Hunter R. Interspecies allometric scaling. In: Cunningham F, Elliott J, Lees P, eds. Handbook of Experimental Pharmacology. Springer Verlag Inc; 2010:139157.

    • Search Google Scholar
    • Export Citation
  • 27.

    Pokras MA, Karas AM, Kirkwood JK, et al. An introduction to allometric scaling and its uses in raptor medicine. In: Redig PT, Coo JE, Remple JD, et al, eds. Raptor Biomedicine. U of Minnesota Press; 1993:211224.

    • Search Google Scholar
    • Export Citation
  • 28.

    Milanova A, Lashev LD. Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species using allometric analysis. Bulg J Vet Med. 2009;12:324.

    • Search Google Scholar
    • Export Citation
  • 29.

    Hunter RP, Isaza R. Concepts and issues with interspecies scaling in zoological pharmacology. J Zoo Wildl Med. 2008;39(4):517526.

  • 30.

    Kukanich B. Clinical interpretation of pharmacokinetic and pharmacodynamic data in zoologic companion animal species. Vet Clin North Am Exot Anim Pract. 2011;14(1):120.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Łebkowska-Wieruszewska B, Barsotti G, Lisowski A, et al. Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs. N Z Vet J. 2017;65(1):1923.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther. 2017;40(3):285292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Baert K, De Backer P. Comparative pharmacokinetics of three non-steroidal anti-inflammatory drugs in five bird species. Comp Biochem Physiol C Toxicol Pharmacol. 2003;134(1):2533.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Rausch-Derra LC, Rhodes L. Safety and toxicokinetic profiles associated with daily oral administration of grapiprant, a selective antagonist of the prostaglandin E2 EP4 receptor, to cats. Am J Vet Res. 2016;77(7):688692.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Jay AR, Krotscheck U, Parsley E, et al. Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs. Am J Vet Res. 2013;74(11):14501456.

    • Crossref
    • Search Google Scholar
    • Export Citation

Appendix 1

Factors and formulas used in metabolic scaling from findings in dogs27 to determine the doses of grapiprant for administration to 6 healthy adult red-tailed hawks (RTHAs; Buteo jamaicensis) during our preliminary study.

  • 1. Calculate the daily minimum energy cost (MEC) of the dogs in the previous study18 with the following formula: MEC = K(BW0.75), where K is the constant for mammals (70) and BW is the mean body weight for the dogs in that study (8 kg). These known values were inserted into the formula:
    article image
  • 2. Calculate the MEC for the RTHAs of the present study with the same formula but with the K constant for non-passerine birds (78) and the RTHAs’ mean body weight of 1.2 kg:
    article image
  • 3. Convert the low-dose treatment (grapiprant, 2 mg/kg) administered to dogs in a previous study18 to an MEC dose with the following formula:
    article image
  • 4. Scale the dog MEC dose to the RTHA dose with the following formula:
    article image

We rounded the scaled dose of 3.57 mg of grapiprant/kg to 4 mg/kg for the lowest dose used in our preliminary study. The same formulas were used for scaling a grapiprant dose of 6 mg/kg administered to dogs in a previous study18 to calculate our middle dose administered to RTHAs during our preliminary study.

article image

We rounded this scaled dose of 10.4 mg/kg grapiprant to 11 mg/kg for the middle dose administered to RTHAs in our preliminary study.

Supplementary Materials

  • Figure 1

    Results of simulations for log-transformed plasma grapiprant concentrations for 1 dose of 20, 25, 30, 35, or 40 mg of grapiprant/kg on the basis of data gathered during a preliminary study in which 6 healthy adult red-tailed hawks (RTHAs; Buteo jamaicensis) were randomly assigned to receive 1 of 3 doses of grapiprant: 4 mg/kg (n = 2), 11 mg/kg (2), or 45 mg/kg (2) after food was withheld for 24 hours.

  • Figure 2

    Log-transformed plasma grapiprant concentration measurements following administration of a single dose of grapiprant (30 mg/kg, PO) at time 0 into the crop of 6 healthy RTHAs from which food had been withheld for 24 hours before treatment. The solid blue line represents the mean ± SD plasma grapiprant concentrations of all 6 RTHAs. The dashed horizontal line represents the plasma grapiprant concentration of 164 ng/mL, which is considered therapeutic in dogs with osteoarthritis.

  • 1.

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    Wendell MD, Sleeman JM, Kratz G. Retrospective study of morbidity and mortality of raptors admitted to Colorado State University Veterinary Teaching Hospital during 1995–1998. J Wildl Dis. 2002;38(1):101106.

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    Tristan T. The aging raptor. Vet Clin North Am Exot Anim Pract. 2010;13(1):5184.

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    Iannone F, Lapadula G. The pathophysiology of osteoarthritis. Aging Clin Exp Res. 2003;15(5):364372.

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    Livingston A. Pain and analgesia in domestic animals. In: Cunningham F, Elliott J, Lees P, eds. Handbook of Experimental Pharmacology. Springer Verlag Inc; 2010:160183.

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    Montesinos A, Ardiaca M, Juan-Sallés C, et al. Effects of meloxicam on hematologic and plasma biochemical analyte values and results of histologic examination of kidney biopsy specimens of African grey parrots (Psittacus erithacus). J Avian Med Surg. 2015;29(1):18.

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  • 7.

    Goessens T, Antonissen G, Croubels S, et al. Nonsteroidal anti-inflammatory drugs in birds: pharmacokinetics, pharmacodynamics and toxicity. Vlaams Diergeneeskd Tijdschr. 2016;85:5562.

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    Hawkins MG, Paul-Murphy J, Guzman DSM. Recognition, assessment, and management of pain in birds. In: Speer BL, ed. Current Therapy in Avian Medicine and Surgery. Elsevier; 2016:616630.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Summa NM, Guzman DSM, Larrat S, et al. Evaluation of high dosages of oral meloxicam in American kestrels (Falco sparverius). J Avian Med Surg. 2017;31(2):108116.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Naidoo V, Swan GE. Diclofenac toxicity in Gyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction. Comp Biochem Physiol C Toxicol Pharmacol. 2009;149(3):269274.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Cuthbert R, Parry-Jones J, Green RE, et al. NSAIDs and scavenging birds: potential impacts beyond Asia’s critically endangered vultures. Biol Lett. 2007;3(1):9093.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Meteyer CU, Rideout BA, Gilbert M, et al. Pathology and proposed pathophysiology of diclofenac poisoning in free-living and experimentally exposed oriental white-backed vultures (Gyps bengalensis). J Wildl Dis. 2005;41(4):707716.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Giorgi M. CJ-023,423 (grapiprant) a potential novel active compound with antihyperalgetic properties for veterinary patients. Am J Anim Vet Sci. 2015;10:5356.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 14.

    Kirkby Shaw K, Rausch-Derra LC, Rhodes L. Grapiprant: an EP 4 prostaglandin receptor antagonist and novel therapy for pain and inflammation. Vet Med Sci. 2015;2(1):39.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Rausch-Derra L, Huebner M, Wofford J, et al. A prospective, randomized, masked, placebo-controlled multisite clinical study of grapiprant, an EP 4 prostaglandin receptor antagonist (PRA), in dogs with osteoarthritis. J Vet Intern Med. 2016;30(3):756763.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Lebkowska-Wieruszewska B, De Vito V, Owen H, et al. Pharmacokinetics of grapiprant, a selective EP4 prostaglandin PGE2 receptor antagonist, after 2 mg/kg oral and i.v. administrations in cats. J Vet Pharmacol Ther. 2017;40(6):e11e15.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17.

    Yokoyama U, Iwatsubo K, Umemura M, et al. The prostanoid EP4 receptor and its signaling pathway. Pharmacol Rev. 2013;65(3):10101052.

  • 18.

    Rausch-Derra LC, Huebner M, Rhodes L. Evaluation of the safety of long-term, daily oral administration of grapiprant, a novel drug for treatment of osteoarthritic pain and inflammation, in healthy dogs. Am J Vet Res. 2015;76(10):853859.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Rausch-Derra LC, Rhodes L, Freshwater L, et al. Pharmacokinetic comparison of oral tablet and suspension formulations of grapiprant, a novel therapeutic for the pain and inflammation of osteoarthritis in dogs. J Vet Pharmacol Ther. 2016;39(6):566571.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    De Vito V, Salvadori M, Poapolathep A, et al. Pharmacokinetic/pharmacodynamic evaluation of grapiprant in a carrageenan-induced inflammatory pain model in the rabbit. J Vet Pharmacol Ther. 2017;40(5):468475.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Knych HK, Seminoff K, McKemie DS. Detection and pharmacokinetics of grapiprant following oral administration to exercised Thoroughbred horses. Drug Test Anal. 2018;10:12371243.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Nakao K, Murase A, Ohshiro H, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322(2):686694.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Budsberg SC, Kleine SA, Norton MM, et al. Comparison of two inhibitors of E-type prostanoid receptor four and carprofen in dogs with experimentally induced acute synovitis. Am J Vet Res. 2019;80(11):10011006.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    de Salazar Alcalá AG, Gioda L, Dehman A, et al. Assessment of the efficacy of firocoxib (Previcox) and grapiprant (Galliprant) in an induced model of acute arthritis in dogs. BMC Vet Res. 2019;15(1):309.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    True random number generator. Random.org. Accessed December 17, 2019. https://www.random.org

  • 26.

    Hunter R. Interspecies allometric scaling. In: Cunningham F, Elliott J, Lees P, eds. Handbook of Experimental Pharmacology. Springer Verlag Inc; 2010:139157.

    • Search Google Scholar
    • Export Citation
  • 27.

    Pokras MA, Karas AM, Kirkwood JK, et al. An introduction to allometric scaling and its uses in raptor medicine. In: Redig PT, Coo JE, Remple JD, et al, eds. Raptor Biomedicine. U of Minnesota Press; 1993:211224.

    • Search Google Scholar
    • Export Citation
  • 28.

    Milanova A, Lashev LD. Comparison of the pharmacokinetics of seven fluoroquinolones in mammalian and bird species using allometric analysis. Bulg J Vet Med. 2009;12:324.

    • Search Google Scholar
    • Export Citation
  • 29.

    Hunter RP, Isaza R. Concepts and issues with interspecies scaling in zoological pharmacology. J Zoo Wildl Med. 2008;39(4):517526.

  • 30.

    Kukanich B. Clinical interpretation of pharmacokinetic and pharmacodynamic data in zoologic companion animal species. Vet Clin North Am Exot Anim Pract. 2011;14(1):120.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Łebkowska-Wieruszewska B, Barsotti G, Lisowski A, et al. Pharmacokinetics and estimated bioavailability of grapiprant, a novel selective prostaglandin E2 receptor antagonist, after oral administration in fasted and fed dogs. N Z Vet J. 2017;65(1):1923.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 32.

    Nagahisa A, Okumura T. Pharmacology of grapiprant, a novel EP4 antagonist: receptor binding, efficacy in a rodent postoperative pain model, and a dose estimation for controlling pain in dogs. J Vet Pharmacol Ther. 2017;40(3):285292.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Baert K, De Backer P. Comparative pharmacokinetics of three non-steroidal anti-inflammatory drugs in five bird species. Comp Biochem Physiol C Toxicol Pharmacol. 2003;134(1):2533.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34.

    Rausch-Derra LC, Rhodes L. Safety and toxicokinetic profiles associated with daily oral administration of grapiprant, a selective antagonist of the prostaglandin E2 EP4 receptor, to cats. Am J Vet Res. 2016;77(7):688692.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35.

    Jay AR, Krotscheck U, Parsley E, et al. Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs. Am J Vet Res. 2013;74(11):14501456.

    • Crossref
    • Search Google Scholar
    • Export Citation

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