Disposition of Deracoxib in Cats After Oral Administration
The pharmacokinetics of deracoxib in seven healthy cats were determined following a single oral (1 mg/kg) dose. Minimal variability among cats was found for all estimated pharmacokinetic variables. Terminal half-life (t1/2) was 7.9 hours. The mean maximum concentration (Cmax) was 0.28 μg/mL and was measured 3.64 hours after drug administration. Deracoxib was not detectable in the plasma after 60 hours. The compounded liquid formula was accepted readily, and no adverse effects were observed. Further studies are needed to determine the efficacy and safety of deracoxib after acute and chronic use in the cat.
Introduction
The use of traditional and selective nonsteroidal anti-inflammatory drugs (NSAIDs) to treat inflammation and pain in the dog and cat is widely accepted. Basic pharmacological and toxicological data for traditional and selective NSAIDs have been determined in a variety of species, with limited information available in cats.1–11 Because rate and extent of reactions that transform drugs are species specific, pharmacological data cannot be extrapolated to the cat from other species.2,12–15
The anti-inflammatory and antipyretic benefits of NSAIDs, as well as potential adverse effects on the gastrointestinal, renal, and hepatobiliary systems, have been established in a variety of species.16–22 The discovery of distinct forms of cyclooxygenase ([COX]; i.e., COX-1, COX-2, and splice variant of COX-1) and the relative effects associated with their inhibition has led to intensive research to identify and develop drugs with a preference for inhibition of COX-2.23–32 In animals, however, improved safety or efficacy has not been demonstrated with the administration of drugs that are preferential COX-2 inhibitors.33
Deracoxib, a diaryl-substituted pyrazole compound, is an NSAID reported to exhibit very high COX-2 selectivity against isolated canine enzymes, with a COX-1:COX-2 ratio of 1275:1.34 But in whole blood, which might be more relevant, the COX-1:COX-2 ration was much lower at only 12.35 Recently, oral formulations (25-mg and 100-mg chewable tablets)a of deracoxib have been approved for use in dogs (>2 kg) for postoperative pain and inflammation. Expression and activity of COX forms probably differ among species, despite the similar structure of these enzymes.36 Therefore, transposing results for potency and selectivity of NSAIDs to cats from other species is not possible.37–39 Studies involving the use of deracoxib in the cat have not been reported. The purpose of this study was to determine the pharmacokinetics of a single oral dose (1 mg/kg) of deracoxib in the cat.
Materials and Methods
Study Animals
Seven, purpose-bred, female cats between 4 and 5 months of age and weighing 1.84 to 2.32 kg (mean 2.06 kg) were used in the study, which was approved by the University Animal Care and Use Committee. Each cat was assessed as healthy based on results of physical examination, a complete blood count (CBC), serum biochemical panel, and urinalysis performed immediately prior to the study. Cats were housed individually and acclimated to the study site for a minimum of 21 days. The cats were fed a standard commercial kitten dietb and water ad libitum.
One day before the beginning of the pharmacokinetic study, cats were premedicated with butorphanol tartratec (0.3 mg/kg intramuscularly [IM]) and acepromazine maleated (0.05 mg/kg IM). The cats were then anesthetized with an initial bolus of propofole (6.6 mg/kg intravenously [IV]) and maintained under anesthesia with propofol at a constant-rate IV infusion of 0.22 mg/kg per minute while breathing room air. A catheterf was inserted into the jugular vein and flushed with heparinized saline (0.9% sodium chloride) solution to maintain patency. At recovery, a neck bandage and protective collarg were placed on each cat to prevent premature removal of the catheter. All cats were offered a commercial dry cat foodb and water 2 hours after catheter placement. Food was withheld 12 hours prior to oral administration of deracoxib.
A single dose of deracoxiba canine oral formulation (1 mg/kg) was administered to each cat. To ensure accurate dosing, a homogeneous oral suspension (5 mg/mL) was compounded from a 25-mg chewable tablet and 5 mL sterile water. The potency was confirmed by high-performance liquid chromatography (HPLC) analysis. To demonstrate distribution of the compound, six different samples were analyzed from the same bottle, and deviation of drug concentration among samples was <8%. On the first day, blood samples (2 mL) were taken prior to and 0.5, 1, 2, 3, 4, 8, 16, 24, 36, 48, 60, and 72 hours after deracoxib administration. The IV catheter was flushed with heparinized saline solution immediately before and after blood collection. To avoid dilution, 2 mL of blood was aspirated from the catheter before withdrawal of each study sample and then reinfused after sample collection. Blood samples were transferred to lithium heparin evacuated collection tubes. Plasma was separated by centrifugation for 5 minutes at ~2000 × g and stored frozen (−70°C) in polypropylene cryo-tubes. Blood samples (3 mL) were taken 24 hours before and 72 hours after deracoxib administration for determination of a CBC and biochemical panel. In addition, a urine sample was collected for analysis by cystocentesis.
Deracoxib Assay
Plasma samples were analyzed by reverse-phase HPLC with ultraviolet detection.40 The HPLC system consisted of 626 solvent delivery system, 717 plus autosampler, and 996 photodiode array detector.h The previously frozen plasma samples were vortexed, and 1 mL from each sample was placed in 15-mL, round-bottom centrifuge tubes followed by 100 μL of tolbutamide (internal standard, 200 μg/mL) and 6 mL of isopropanol:chloroform (80:20). Tubes were placed on a tube rocker for 15 minutes and then centrifuged at 1000 g for 15 minutes. Supernatants were transferred to a clean tube, and the organic phase was evaporated at 30°C with nitrogen. Samples were reconstituted in 1 mL of mobile phase, and a 100-μL injection was analyzed. The compounds were separated on an Atlantis DC18 (4.6 × 150 mm, 5 μm) column with an Atlantis C18 guard column.h The mobile phase was a mixture of 10 mM potassium phosphate buffer (pH 4.5): acetonitrile (52:48). The flow rate was 1 mL every minute, and the column temperature was 30°C. Ultraviolet absorbance was measured at 252 nm.
Standard curves for plasma analysis were prepared by spiking pooled feline plasma with deracoxib (100% purity)i to produce a linear concentration range of 10 to 1500 ng/mL. The calibration samples were processed and prepared exactly as described for the actual plasma samples. Recovery ranged from 85% to 100%. Intra-assay variability ranged from 1.2% to 3.4%, while interassay variability was 5.8% to 11.1%. The limit of quantification was 0.01 μg/mL.
Pharmacokinetic Studies
Deracoxib plasma concentrations were plotted on a semilog-arithmic scale to examine the shape of the curve for preliminary selection of an appropriate model. Pharmacokinetic parameters were determined for each individual animal using a commercial software program.j Noncompartmental values included maximum concentration (Cmax), time of maximum concentration (Tmax), terminal half-life (t1/2), area under the plasma concentration time curve (AUC), and area under the first moment time curve (AUMC). The AUC and AUMC were calculated using the trapezoidal rule up until the last measurable concentration, with extrapolation to infinity. Mean residence time was calculated as AUMC0–∞/AUC0–∞.
Data Analysis
Results from CBCs, biochemical panels, and urinalyses taken before and at 72 hours after deracoxib administration were averaged. Statistical analysisk was performed using paired t-tests to determine significant (P<0.05) differences between groups.
Results
The compounded liquid formula was accepted readily by all cats. No identifiable adverse reactions occurred following administration of deracoxib in any of the subjects. All cats continued to eat, drink, and maintain their body weight throughout the study period.
Pharmacokinetic parameters determined for a single (1 mg/kg) oral dose of deracoxib in these cats are listed in Table 1. Mean Cmax was 0.28 μg/mL and was measured 3.64 hours after drug administration. Terminal half-life was 7.9 hours. There were no detectable levels of drug in cat plasma after 60 hours [see Figure]. Statistically significant differences were seen in averaged results of red blood cell counts, packed cell volume, hemoglobin content, and concentrations of serum albumin, alkaline phosphatase, phosphorus, and calcium before deracoxib administration, as compared to results after deracoxib administration [Table 2]. Mean values for all urine, hematological, and biochemical tests, however, were within normal limits before and after deracoxib administration.
Discussion
Pharmacokinetic data on deracoxib after oral administration to cats have not been previously published. Determination of bioavailability and other pharmacokinetic parameters, such as clearance and volume of distribution, would have been possible with IV administration; however, an IV formulation was not available at the time of the study. The dose of deracoxib selected for this study was based on the standard recommended dose (1 to 2 mg/kg q 24 hours) for dogs with chronic osteoarthritis.a Deracoxib was well tolerated by the cats at the 1 mg/kg dose; however, long-term studies evaluating biochemical parameters and gastric mucosal integrity are necessary to determine safety of the drug in cats.
Although laboratory parameters were within normal limits at all times, cats had lower red blood cell counts, packed cell volumes, hemoglobin, and albumin concentrations 72 hours after deracoxib administration. These decreases were attributed to blood loss that occurred during sample collection. Decreased calcium concentrations after deracoxib administration probably reflected lowered albumin concentrations.41 Differences in serum alkaline phosphatase activity and phosphorous concentrations were statistically significant but clinically irrelevant. Similarly, no hematological or biochemical abnormalities were noted in dogs after administration of deracoxib at 1 to 2 mg/kg q 24 hours for 43 days.a In a recent retrospective study, 16 (55%) of 29 dogs were found to have gastrointestinal tract perforation in association with deracoxib administration.42 However, subjects were administered deracoxib at a dose higher than that approved for the indication being treated, and, as a result, the association between the use of the deracoxib and the induction of gastrointestinal ulceration remains unclear.
Pharmacokinetic parameters of oral deracoxib have been previously established in dogs.a In cats, deracoxib had a Tmax of 3.64 hours after dosing, which was longer than that reported in dogs (i.e., 2 hours). Mean half-life of deracoxib after oral administration in cats was 7.9 hours, which was much longer than the mean half-life (i.e., 3 hours) reported in dogs.a A similar species-specific response is reported with the NSAID carprofen, which has approximate half-lives of 9 hours in dogs and 20 hours in cats.43,44 A dose of 1 mg/kg deracoxib produced a much longer t1/2 in cats than in dogs, possibly because of differences in rate and extent of metabolism. Nonlinear elimination kinetics have been demonstrated in dogs administered >8 mg/kg per day, resulting in a greater rise in deracoxib plasma concentrations than would be expected with a proportional increase in dosage.a Competitive inhibition of COX-1 can occur when higher-than-recommended doses are administered, leading to increased toxicity, which could also occur in cats.11 Variability was noted in the data of this study. Two cats had no measurable drug concentrations after 24 hours, and the Tmax was greatly decreased (0.5 hours) for one cat and greatly increased (8 hours) for another cat compared to the other test subjects. These oddities may have reflected differences in oral disposition of the drug in some animals. Variable metabolism of the drug has also been noted in dogs.a
In the study reported here, disposition of deracoxib was evaluated only in young, female intact cats. Differences in drug kinetics may occur between males and females; therefore, results of deracoxib disposition could vary if studied in different genders and ages of cats.
Conclusion
In cats, oral deracoxib reached maximum blood concentrations 3.6 hours after administration and had a mean half-life of approximately 8 hours. Therapeutic potential and dosage intervals, however, were not determined in this study. Although no adverse effects were noted, future studies evaluating gastric mucosal integrity and renal and hepatic function are necessary to determine the safety of this drug following acute and chronic usage in cats.
Deramaxx and product information; Novartis Animal Health US, Inc., Greensboro, NC 27408
Hill’s Kitten Original; Hill’s Pet Nutrition, Inc., Topeka, KS 66601
Torbugesic; Fort Dodge Animal Health, Fort Dodge, IA 50501
Acepromazine; Boehringer Ingelheim Vetmedica, Inc., St. Joseph, MO 64506
Diprivan; Stuart Pharmaceuticals, Wilmington, DE 19801
Venocath-16; Abbott, Ireland, Sligo, Republic of Ireland
3M™ Clear Custom Collar 1450C; 3M Worldwide, St. Paul, MN 55101
HPLC system; Waters, Milford, MA 01757
Deramaxx Analytical Sample; Novartis Animal Health US, Inc., Greensboro, NC 27408
WinNonlin, version 4.1; Pharsight Corp., Mountain View, CA 94035
Stats View, version 2.0; SAS Institute, Inc., Cary, NC 27513
Citation: Journal of the American Animal Hospital Association 42, 3; 10.5326/0420212
Mean (± standard deviation) plasma concentration (μg/mL) of deracoxib over 60 hours after seven cats were each administered a single oral dose (1 mg/kg).
