Pharmaco*kinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days (2024)

Pain relief is one of the basic tenants of veterinary medicine, and veterinarians are constantly striving to improve their ability to alleviate pain in their patients. One of the most common classes of drugs used by veterinarians for analgesia is NSAIDs.¹ These drugs work centrally and peripherally to prevent pain and have analgesic and anti-inflammatory effects.^2,3 They are used to prevent and treat postoperative pain, most often associated with musculoskeletal disease.^4–7 Results of several studies^8–10 have indicated that NSAIDs are effective in treating postoperative pain in dogs and cats, without producing adverse effects such as sedation, ileus, dysphoria, and hypothermia, which are typically associated with opioids and can be profound. The NSAIDs reduce inflammation by inhibition of the action of COX enzymes, which convert arachidonic acid into prostanoids.^1,4,8 Cyclooxygenase has 2 forms, COX-1 and COX-2. The form associated with homeostasis, COX-1, produces eicosanoids that are often protective. Although COX-2 is the form of the enzyme most often associated with inflammation, homeostatic effects of COX-2 eicosanoids, including maintenance of gastrointestinal, platelet, and renal function, are also important. Therefore, toxic effects of NSAIDs are most commonly associated with nonselective inhibition of both COX-1 and COX-2, whereas analgesia associated with NSAIDs is primarily attributable to inhibition of COX-2,^1,8,10–14 and an approach to achieving the desired effect of analgesia is to specifically target the inhibition of COX-2 while maintaining activity of COX-1 to provide the beneficial effects of eicosanoids.

The adverse effects associated with NSAIDs most commonly involve gastrointestinal tract injury and, occasionally, impairment of renal blood flow.^4,11,15 Gastrointestinal perforation, ulceration, and bleeding have been associated with NSAID-induced depression of normal prostaglandin E₂-mediated mucosal protective mechanisms as well as direct local irritation.^11,15 Because maintenance of gastrointestinal mucosal integrity is largely the result of COX-1 activity, COX-2 selective NSAIDs are associated with fewer gastrointestinal complications.¹¹ Nonsteroidal anti-inflammatory drugs may also cause nephropathy, especially with chronic use.¹¹ Acute hepatic toxicity has been reported in several breeds of dogs but occurs much less frequently than adverse gastrointestinal and renal effects.¹⁶ Because NSAIDs have the potential to produce adverse gastrointestinal effects, the concurrent use of other NSAIDs or corticosteroids (which also produce adverse gastrointestinal effects) is not recommended.¹⁴ The adverse effects of NSAIDs are usually dose dependent, so it is important to know the pharmaco*kinetics of each medication before it is used in a particular species.¹⁷

Recently, meloxicam, a COX-2 selective NSAID, has become more frequently administered in veterinary medicine. Meloxicam's anti-inflammatory, analgesic, and antipyretic properties have been established in experimental and clinical studies in dogs and cats.^5–10,12 Because of meloxicam's COX-2 selectivity, its use may be associated with a decreased occurrence of adverse effects such as inhibition of platelet function and adverse gastrointestinal effects.^1–3,11 Meloxicam is metabolized extensively in the liver into 4 metabolites, none of which have anti-inflammatory or analgesic properties.^3,17

Safe and effective pain relief should ideally be based on sound research that has been conducted to determine a therapeutic dose that does not cause adverse effects. The plasma or serum half-life of meloxicam is species specific, and it is difficult to extrapolate data across species.^{2,6,11,14,17,18} However, there are very few research studies on the pharmaco*kinetics of NSAIDS in exotic small animal species. Where data are available, they are often derived from studies in rodents. In particular, despite their popularity as companion animals, few studies on NSAIDs have been performed in rabbits (Oryctolagus cuniculus), and only 3 studies^2,17,19 on the pharmaco*kinetics of meloxicam in this species have been reported. In 1 recent study,¹⁹ the pharmaco*kinetics of meloxicam in rabbits after oral administration (1.0 mg/kg, q 24 h, for 5 days) was determined. The results of that study¹⁹ indicated that peak plasma concentrations of meloxicam at the described dose were similar to therapeutic concentrations in other species. Considering those results, a dose of 1.0 mg/kg, PO, was hypothesized to be necessary to reach therapeutic concentrations of meloxicam in rabbits. However, because of the possibility that meloxicam could accumulate in plasma or tissues with multiple doses, this dosage needed to be evaluated to demonstrate clinical safety beyond 5 days of use.

The objectives of the study reported here were to determine the pharmaco*kinetics and safety of meloxicam in rabbits at a dosage of 1 mg/kg, PO, every 24 hours for a 29-day period. We performed plasma biochemical analysis and gross and histologic examinations to assess possible adverse effects of the drug at this dosage. Our hypotheses were that administration of meloxicam under this regimen would cause high plasma concentrations of the drug and that meloxicam concentrations would accumulate in plasma during the treatment period. We also hypothesized that there would be no adverse biochemical, gross, or histopathologic effects of meloxicam at this dosage.

Materials and Methods

Animals—Six clinically normal 3-month-old New Zealand white rabbits (Oryctolagus cuniculus; body weight range, 2.55 to 2.71 kg) were included in the study. The rabbits were obtained from a commercial source and were specific pathogen (Pasteurella spp) free. Rabbits were housed individually at the research facilities of the Kansas State University College of Veterinary Medicine with constant temperature (21.11°C) and humidity (60%) and were exposed to cycles of 16 hours of light and 8 hours of darkness/d. Rabbits were fed a timothy-based pelleted diet^a and timothy hay.^b Water was available ad libitum. Rabbits were acclimated to the facility for 5 days after their arrival and were habituated to handling prior to initiation of the study.

Immediately prior to the start of the study, each rabbit underwent a physical examination, including evaluation of a fecal sample, urinalysis, and collection of a blood sample (0.5 mL) from a lateral saphenous vein or auricular artery for determination of Hct, plasma total protein, and biochemical variables (glucose, BUN, creatinine, total protein, albumin, globulin, total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations, with creatine kinase, alanine transaminase, and alkaline phosphatase activities). All rabbits were determined to be healthy and behaviorally normal. The study was approved by the Institutional Animal Care and Use Committee of Kansas State University.

Experimental design and sample collection—Meloxicam solution^c (1.0 mg/kg, PO) was administered to each rabbit; a 3-mL syringe containing the appropriate dose of meloxicam was inserted into the diastema, and the drug was slowly administered so that none of the medication escaped the oral cavity. Rabbits received meloxicam (1 mg/kg, PO) every 24 hours. The frequency of meloxicam administration in the present study was determined on the basis of results of other studies^2,17,19 performed to evaluate pharmaco*kinetics of meloxicam in rabbits. Also, the use of this meloxicam administration interval enabled assessment of meloxicam accumulation in plasma over time.

Blood samples were collected from a lateral saphenous vein or an auricular artery of each rabbit with a 25-gauge butterfly catheter and a syringe containing heparin. Blood was collected immediately before (0 hours) and 2, 4, 6, 8, and 24 hours after daily meloxicam administration on days 1, 8, 15, 22, and 29. Blood was also collected 36 hours after the final dose of meloxicam was given on day 29. At each time 0 and at the 36-hour time point after dose 29, 1.5 mL of blood was collected to allow for plasma biochemical analysis and evaluation of PCV and total solids as well as pharmaco*kinetic analysis. At every other time point, 0.5 mL of blood was collected for the pharmaco*kinetic assay. Therefore, 31 blood samples were collected from each rabbit during the study period for determination of meloxicam concentrations. Within 20 minutes after each collection, blood samples were centrifuged (10 minutes at approx 2,000 × g), and the plasma supernatant was harvested and stored at −70°C until analysis.

Behavior, attitude, mentation, activity, urinary and fecal output, and amount of food and water consumed by the rabbits were subjectively monitored by 1 investigator (KWD) on a daily basis. Rabbits were weighed weekly.

Plasma biochemical analysis—Plasma biochemical analytes were measured at baseline (before meloxicam administration) and weekly during the study as indicated. These analytes included plasma glucose, BUN, creatinine, total protein, albumin, globulin (calculated), total calcium, phosphorus, sodium, potassium, chloride, bicarbonate, cholesterol, and total bilirubin concentrations and creatine kinase, alanine transaminase, and alkaline phosphatase activities.

Postmortem evaluation—All rabbits were euthanatized by administration of pentobarbital sodium (100 mg/kg, IV), and cadavers were transported immediately to a necropsy room where postmortem examinations were initiated ≤ 15 minutes after euthanasia. The rabbits were examined externally and internally for gross abnormalities.

As tissues were examined, samples were collected and placed in neutral-buffered 10% formalin solution for subsequent histologic examination. Samples collected from all rabbits included lung, trachea, liver, spleen, kidneys, urinary bladder, salivary glands, mesenteric lymph nodes, esophagus, fundic and pyloric regions of stomach, small intestine, cecum, appendix, large colon, small colon, heart, skeletal muscles, adrenal glands, pancreas, and bone marrow. Multiple sections of each region of the intestine were collected; small intestinal sections with and without Peyer's patches were included. After fixation for 48 hours, the tissues were trimmed, placed into cassettes, routinely processed, and embedded into paraffin blocks. Tissues were cut at 4-μm thickness, mounted on glass slides, and stained with H&E. A board-certified veterinary pathologist (JCN) examined the slides and performed further testing with special stains when needed.

Plasma meloxicam analysis—Plasma concentrations of meloxicam were determined by means of high-pressure liquid chromatography^d and triple quadrupole mass spectrometry, as previously described in detail.¹⁹ The plasma standard curve and quality control standards were made with untreated rabbit plasma. The standard curves were linear between 0.025 and 5 μg/mL and accepted if the correlation coefficient was > 0.99 and predicted concentrations were within 15% of the actual concentration for ≥ 5/6 standards. Accuracy of the assay was 99%, 107%, and 102% of the actual concentration in replicates of 5 quality-control samples for meloxicam concentrations of 0.025, 0.5, and 5 μg/mL, respectively. The coefficient of variation was 7%, 6%, and 4% on replicates of 5 quality control samples for concentrations of 0.025, 0.5, and 5 μg/mL, respectively.

Pharmaco*kinetic analysis—Pharmaco*kinetic parameters of meloxicam were estimated with computer software.^f The AUCinf and AUC_0–24 were determined by use of the linear trapezoidal rule. The Cmax and time to maximum plasma concentration were determined directly from the data. The terminal half-life after the last dose was determined from meloxicam concentrations measured in samples collected at the last 3 time points (ie, 8, 24, and 36 hours after the final dose of meloxicam on day 29) by means of log linear regression. A standard 2-stage approach was used to present the mean and SD pharmaco*kinetic parameters. Pharmaco*kinetic parameters were determined for each individual animal, and then the mean and SD were determined for each dose from the individuals' pharmaco*kinetic parameters.

Statistical analysis—Results of a Shapiro-Wilk test revealed that pharmaco*kinetic parameters were normally distributed and of equal variance. Therefore, a 1-way repeated-measures ANOVA was used to assess the data.^g A Tukey test was used for the all-pairwise comparison procedure on each day pharmaco*kinetic parameters were determined. Values of P < 0.05 were considered significant.

Results

Meloxicam was easily administered to each rabbit, and all rabbits remained apparently healthy during the study. None of the rabbits had changes in behavior, attitude, mentation, amount of activity, amount of food or water consumed, or urinary or fecal production that could be attributed to an adverse drug reaction. All values measured in the plasma biochemical analysis before and during the study were within published reference ranges.²⁰ The mean ± SD body weight of the rabbits at the end of the study was 2.70 ± 0.1 kg.

During gross necropsy and histologic evaluation, special attention was given to organs that have been reported to show lesions related to meloxicam toxicosis, including the liver, urinary bladder, gastrointestinal tract, and kidneys.^4,11,15 The liver of 1 rabbit had a single irregular white nodule that contained coalescing areas of necrotic debris surrounded by bands of macrophages, lymphocytes, and heterophils. A Gram stain and silver stain did not reveal the presence of bacteria or fungi, including yeast. The inflammation was consistent with a localized infection. No lesions suggestive of acute or chronic meloxicam toxicosis were found in any of the rabbits.

Mean ± SD plasma concentrations of meloxicam in samples collected after doses 1, 8, 15, 22, and 29 were summarized (Figure 1). Mean ± SD daily Cmax for meloxicam was 0.67 ± 0.19 μg/mL, 0.81 ± 0.21 μg/mL, 1.00 ± 0.31 μg/mL, 1.00 ± 0.29 μg/mL, and 1.07 ± 0.19 μg/mL, respectively (Table 1). There was no unexpected plasma accumulation of meloxicam over the 29-day dosing period. The mean time to maximum plasma concentration in samples collected after doses 1, 8, 15, 22, and 29 was 6.3 ± 0.8 hours, 5.3 ± 1.0 hours, 4.7 ± 1.0 hours, 5.0 ± 1.1 hours, and 4.3 ± 0.8 hours, respectively. There was no significant difference between doses 8, 15, 22, and 29 for any parameter, indicating no apparent effect of chronic dosing on drug exposure (as measured with the area under the plasma concentration-versus-time curve) or on Cmax other than predicted accumulation with multiple-dose administration.

Pharmaco*kinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days (2)

Table 1—

Mean ± SD pharmaco*kinetic parameters of meloxicam in 6 healthy rabbits following administration of the drug (1.0 mg/kg, PO, q 24 h) for 29 days.

	Dose
Parameter	1	8	15	22	29
AUC_0–24 (h•μg/mL)	8.81 ± 2.45	10.90 ± 2.93	11.41 ± 2.74	11.69 ± 2.46	12.43 ± 1.61
Cmax (μg/mL)	0.67 ± 0.19^a	0.81 ± 0.21	1.00 ± 0.31	1.00 ± 0.29	1.07 ± 0.19^a
Tmax (h)	6.3 ± 0.8^a,b	5.3 ± 1.0	4.7 ± 1.0^a	5.0 ± 1.1	4.3 ± 0.8^b
T_1/2 (h)	NA	NA	NA	NA	7.2 ± 0.6
AUCinf (h•μg/mL)	10.14 ± 3.2	NA	NA	NA	NA

NA = Not applicable. T_1/2 = Terminal half-life. Tmax = Time to maximum plasma concentration.

^a,bWithin a row, the same superscript letters indicate significant (P < 0.05) differences among time points.

Discussion

Findings of the present study indicated that oral administration of meloxicam at a dose of 1.0 mg/kg every 24 hours for 29 days to rabbits resulted in plasma meloxicam concentrations similar to those reported in a previous study¹⁹ where investigators evaluated the short-term use of meloxicam at a dose of 1.0 mg/kg every 24 hours for 5 days in rabbits. However, the plasma meloxicam concentrations in this study and the previous study were proportionally higher than those attained after administration of the currently recommended^2,17 dose (0.2 to 0.3 mg/kg). The clinical efficacy of meloxicam in rabbits was not determined in the present study, and further studies are needed in which the efficacy of orally administered meloxicam at a dose of 1 mg/kg in rabbits is assessed.

Results of the study¹⁹ in which the pharmaco*kinetics of meloxicam administered to rabbits by the same route and at the same dosage as in the present study was determined indicated a mean Cmax of 0.83 μg/mL and AUCinf of 10.37 h•μg/mL. Results of the present study indicated similar plasma values after 1 dose of meloxicam (Cmax, 0.67 ± 0.19 μg/mL; AUCinf, 10.14 ± 3.2 h•μg/mL). Results for these parameters in the present study and the previous study¹⁹ were both proportionally higher than the Cmax (0.17 ± 0.06 μg/mL) and AUCinf (1.8 ± 0.50 h•μg/mL) of meloxicam in an earlier study,² in which a dose of 0.2 mg/kg was investigated in rabbits. These findings indicate that an increase in an orally administered dose of meloxicam from 0.2 to 1.0 mg/kg caused a proportional increase in the plasma concentration of the drug. The higher mean Cmax values observed in this study and in the previous study¹⁹ for the same dose are notable because they are similar to the Cmax values for clinically effective doses of meloxicam in other species.^21,22 It is interesting to note that although the plasma concentrations of meloxicam after administration of clinically effective doses in other species seem to be similar to those in rabbits after administration at a dose of 1.0 mg/kg, PO, in the present study and the previous study, the effective doses of meloxicam for those other species were much lower than the dose administered to rabbits in our study. Therefore, it appears necessary to administer a much higher dose of meloxicam to rabbits to achieve similar plasma concentrations of meloxicam. Meloxicam appears to have variable efficacy among species, so extrapolation of data for other species should be discouraged.

Results of plasma biochemical analysis in the present study did not reveal any values outside of normal reference ranges. The main adverse effects of NSAIDs occur in the gastrointestinal tract and renal system, so special attention was given to BUN and creatinine concentrations and alanine aminotransferase and alkaline phosphatase activities, but no clinically important differences were noted among pretreatment plasma samples and samples taken during the treatment period because all remained within the reference ranges. Packed cell volume, total solids, and body weight were all measured weekly, and no appreciable difference was noted in any of the values (other than apparent weight gain). In addition, there were no observable changes in the behavior, appetite, or urinary or fecal output of rabbits during the study. No clinically relevant changes were seen on gross necropsy of the rabbits, and there were no changes attributable to meloxicam found on histologic examination. These results suggest that the dosage of 1.0 mg of meloxicam/kg, PO, every 24 hours may be safe for use in rabbits up to 29 days. However, although no unexpected drug accumulation and no adverse effects were detected in the healthy animals used in our study, sick animals receiving meloxicam must be closely monitored because drug clearance may be impaired.

Very few NSAIDs are approved for long-term use in veterinary patients, but animals frequently need pain medication over an extended period of time. Meloxicam is a popular pain medication for use in rabbits because it is available in a palatable liquid formulation, is not a controlled substance, and is well tolerated in most species. In the present study, administration of the drug at 1.0 mg/kg, PO, every 24 hours appeared to be well tolerated, but further study is needed to determine clinical efficacy and clearance at this dose in rabbits.

ABBREVIATIONS

AUC_0–24	Area under the plasma concentration-versus-time curve from administration of the last dose to 24 hours after administration of the last dose
AUCinf	Area under the plasma concentration-versus-time curve extrapolated to infinity after administration of a single dose
Cmax	Observed maximum plasma concentration

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References

1. Streppa HK, Jones CJ, Budsberg SC. Cyclooxygenase selectivity of nonsteroidal anti-inflammatory drugs in canine blood. Am J Vet Res 2002; 63: 91–94.
- Crossref
- Search Google Scholar
- Export Citation
2. Carpenter JW, Pollock CG, Koch DE, et al. Single and multiple-dose pharmaco*kinetics of meloxicam after oral administration to the rabbit (Oryctolagus cuniculus). J Zoo Wildl Med 2009; 40: 601–606.
- Crossref
- Search Google Scholar
- Export Citation
3. Davies NM, Skjodt NM. Clinical pharmaco*kinetics of meloxicam; a cyclo-oxygenase-2 preferential nonsteroidal anti-inflammatory drug. Clin Pharmaco*kinet 1999; 36: 115–126.
- Search Google Scholar
- Export Citation
4. Luna SPL, Basilio AC, Steagall PVM, et al. Evaluation of adverse effects of long-term oral administration of carprofen, etodolac, flunixin meglumine, ketoprofen, and meloxicam in dogs. Am J Vet Res 2007; 68: 258–264.
- Crossref
- Search Google Scholar
- Export Citation
5. Peterson KD, Keefe TJ. Effects of meloxicam on severity of lameness and other clinical signs of osteoarthritis in dogs. J Am Vet Med Assoc 2004; 225: 1056–1060.
- Crossref
- Search Google Scholar
- Export Citation
6. Doig PA, Purbrick KA, Hare JE, et al. Clinical efficacy and tolerance of meloxicam in dogs with chronic osteoarthritis. Can Vet J 2000; 41: 296–300.
- Search Google Scholar
- Export Citation
7. Moreau M, Dupuis J, Bonneau NH, et al. Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis. Vet Rec 2003; 152: 323–329.
- Crossref
- Search Google Scholar
- Export Citation
8. Caulkett N, Read M, Fowler D, et al. A comparison of the analgesic effects of butorphanol with those of meloxicam after elective ovariohysterectomy in dogs. Can Vet J 2003; 44: 565–570.
- Search Google Scholar
- Export Citation
9. Carroll GL, Howe LB, Peterson KD. Analgesic efficacy of preoperative administration of meloxicam or butorphanol in onychectomized cats. J Am Vet Med Assoc 2005; 226: 913–919.
- Crossref
- Search Google Scholar
- Export Citation
10. Mathews KA, Pettifer G, Foster R, et al. Safety and efficacy of preoperative administration of meloxicam, compared with that of ketoprofen and butorphanol in dogs undergoing abdominal surgery. Am J Vet Res 2001; 62: 882–888.
- Crossref
- Search Google Scholar
- Export Citation
11. Jones CJ, Budsberg SC. Physiologic characteristics and clinical importance of the cyclooxygenase isoforms in dogs and cats. J Am Vet Med Assoc 2000; 217: 721–729.
- Crossref
- Search Google Scholar
- Export Citation
12. Jones CJ, Streppa HK, Harmon BG, et al. In vivo effects of meloxicam and aspirin on blood, gastric mucosal, and synovial fluid prostanoid synthesis in dogs. Am J Vet Res 2002; 63: 1527–1531.
- Crossref
- Search Google Scholar
- Export Citation
13. Engelhardt G. Pharmacology of meloxicam, a new non-steroidal anti-inflammatory drug with an improved safety profile through preferential inhibition of COX-2. Rheumatology 1996; 35 (suppl 1): 4–12.
- Crossref
- Search Google Scholar
- Export Citation
14. Curry SL, Cogar SM, Cook JL. Nonsteroidal antiinflammatory drugs: a review. J Am Anim Hosp Assoc 2005; 41: 298–309.
- Crossref
- Search Google Scholar
- Export Citation
15. Forsyth SF, Guilford WG, Haslett SJ, et al. Endoscopy of the gastroduodenal mucosa after carprofen, meloxicam and ketoprofen administration in dogs. J Small Anim Pract 1998; 39: 421–424.
- Crossref
- Search Google Scholar
- Export Citation
16. MacPhail CM, Lappin MR, Meyer DJ, et al. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. J Am Vet Med Assoc 1998; 212: 1895–1901.
- Search Google Scholar
- Export Citation
17. Turner PV, Chen HC, Taylor MW. Pharmaco*kinetics of meloxicam in rabbits after single and repeat oral dosing. Comp Med 2006; 56: 63–67.
- Search Google Scholar
- Export Citation
18. Toutain PL, Reymond N, Laroute V, et al. Pharmaco*kinetics of meloxicam in plasma and urine of horses. Am J Vet Res 2004; 65: 1542–1547.
- Crossref
- Search Google Scholar
- Export Citation
19. Fredholm DV, Carpenter JW, KuKanich B, et al. Pharmaco*kinetics of meloxicam in rabbits after oral administration of single and multiple doses. Am J Vet Res 2013; 74: 636–641.
- Crossref
- Search Google Scholar
- Export Citation
20. Fiorello CV, Divers SJ. Rabbits. In: Carpenter JW, ed. Exotic animal formulary. 4th ed. St Louis: Elsevier, 2012;517–559.
- Search Google Scholar
- Export Citation
21. Montoya L, Ambrose L, Kreil V, et al. A pharmaco*kinetic comparison of meloxicam and ketoprofen following oral administration to healthy dogs. Vet Res Commun 2004; 28: 415–428.
- Crossref
- Search Google Scholar
- Export Citation
22. Giraudel JM, Diquelou A, Laroute V, et al. Pharmaco*kinetic/pharmacodynamic modelling of NSAIDs in a model of reversible inflammation in the cat. Br J Pharmacol 2005; 146: 642–653.
- Crossref
- Search Google Scholar
- Export Citation