Abstract
Objective
Determine pharmacokinetic parameters of meloxicam in red kangaroos following a single IM or PO dose.
Methods
In the spring of 2024, following a pilot study to determine the appropriate dosage, a managed population of clinically healthy adult or subadult red kangaroos at the Nashville Zoo received a 0.2-mg/kg dose of meloxicam, IM or PO. Four additional kangaroos received a 0.2-mg/kg dose of meloxicam, IV, to establish bioavailability. Blood samples were obtained under manual restraint over 48 hours, using a sparse sampling method. Plasma meloxicam concentration was determined using HPLC. Plasma meloxicam time-concentration profiles were established using a non-compartmental pharmacokinetic analysis.
Results
15 kangaroos were included in this study. Eight kangaroos were assigned to the IM group, and 8 were assigned to the PO group. Pharmacokinetic parameters were time to the maximum observed plasma concentration (tmax) = 0.5 hours, maximum plasma concentration (Cmax) = 1.071 μg/mL, terminal half-life (t½) = 13.03 hours, elimination rate constant (λz) = 0.05 1/h, area under the plasma concentration-versus-time curve from time 0 to last point (AUC0–last) = 11.643 h·μg/mL, area under the plasma concentration-versus-time curve from time 0 to infinity (AUC0–∞) = 12.460 h·μg/mL, bioavailability = 129%, and apparent volume of distribution after extravascular administration (V/F) = 234 mL/kg, and tmax = 6 hours, Cmax = 0.445 μg/mL, t1/2 = 9.90 hours, λz = 0.07 1/h, AUC0–last = 6.666 h·μg/mL, AUC0–∞ = 7.023 h·μg/mL, bioavailability = 73%, and V/F = 557 mL/kg for the IM and PO groups, respectively. One kangaroo collapsed and died approximately 15 minutes following administration of an IV dose of meloxicam. Necropsy revealed intracranial hemorrhage.
Conclusions
The Cmax and t1/2 of meloxicam were greater in the IM group than the PO group. When dosed IM, plasma meloxicam concentrations reached levels reported to be therapeutic in other species, while this was inconsistently achieved with PO dosing.
Clinical Relevance
IM meloxicam may offer advantages to PO dosing due to the greater Cmax and longer t1/2. Nonsteroidal anti-inflammatory drugs are known to decrease platelet function, and it is unknown if red kangaroos are at increased risk for hemorrhage following the administration of meloxicam compared to other species.
Red kangaroos (Osphranter rufus) are marsupials and members of the family Macropodidae. Commonly housed in zoological institutions and occasionally kept as pets, they frequently experience ailments such as macropod progressive periodontal disease, trauma, and infections that cause pain and inflammation.1,2 Despite the ubiquity of this species in the wild in Australia and in zoos throughout the world, published pharmacological data on kangaroos are not available. Among macropods, only wallabies have been the subject of pharmacological investigations.3–5 Given the relatively common presence of red kangaroos in human care, developing a deeper understanding of NSAIDs in these animals is necessary to improve analgesic therapy.
Meloxicam is a NSAID that preferentially inhibits the cyclooxygenase-2 isoenzyme, exerting anti-inflammatory, analgesic, and antipyretic effects.6 It is frequently used and well studied across veterinary medicine, including in another Australian marsupial, koalas (Phascolarctos cinereus).7–10 Marsupials have been shown to possess lower basal and field metabolic rates than placental mammals,11–12 which historically led to speculation that drug dosages, when extrapolated from placental mammals, could be administered at lower doses in marsupials and still achieve desired effects.13 Additionally, kangaroos possess complex gastrointestinal systems that rely on an array of symbiotic microbes to extract metabolizable energy,14–15 and the effect of their complex stomach on PO-dosed drugs is unknown. Given the unique physiological and anatomical characteristics of these animals, species-specific dosing regimens are needed.
The aim of this study was to establish pharmacokinetic parameters of meloxicam following a single dose administered IM or PO at 0.2 mg/kg in red kangaroos.
Methods
Animals
Fifteen clinically healthy subadult to adult red kangaroos comprised of 12 females and 3 males were included in this study following initial health assessments. Body weights and ages ranged from 12.2 to 31.8 kg and 1.5 to 13 years old. Each animal was manually restrained for physical examination and phlebotomy for CBC, serum biochemistry panel, and Toxoplasma gondii serology. Based on the results of those exams, all kangaroos were determined to be healthy and without a joey present in the pouch before inclusion in the study.
Experimental design and sample collection
All animal handling and sampling were approved by the Nashville Zoo IACUC. Noncompartmental pharmacokinetic analysis using the sparse sampling option was carried out for this study.
Pilot study—An initial pilot study consisting of 4 individuals (2 male and 2 female) was conducted to confirm the study protocol and analysis. A pilot dose of 0.2 mg/kg was chosen based on the most common dosage used by zoo veterinarians as obtained through the Zoological Information Management System.16 To administer doses and collect blood samples, individual kangaroos were manually restrained by the animal care team, with the first team member lifting and supporting the kangaroo underneath the abdomen and chest, the second team member controlling the tail, and the third team member controlling the forelimbs. Doses of meloxicam (injectable: OstiLox, Norbrook Laboratories Ltd; oral: Meloxidyl, MWI) were administered by the veterinary team. Oral doses were administered via a plastic oral syringe directly into the oral cavity while controlling the head to ensure complete ingestion. Injectable doses were administered by hand injection using a 22-gauge, 1-inch needle on a 3-mL luer-lock syringe either IM in the caudal thigh or IV in the lateral saphenous vein. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 48 hours after dosing, and analysis of the pilot samples indicated that an additional sampling time at 0.25 hours for the IM and IV groups was necessary to appropriately build the pharmacokinetic profile when conducting the main study. The sampling times for the PO group remained unchanged from the pilot study to the main study. Kangaroos were kept in an indoor barn comprised of two 30-ft X 30-ft stalls between sampling time points.
Main study—Two groups composed of 8 individuals each were sampled for this portion of the study, with 1 group receiving meloxicam IM and the other PO. Four additional kangaroos received IV meloxicam to calculate absolute bioavailability. A minimum 14-day washout period occurred between doses of meloxicam for any kangaroo used in multiple study groups.
Samples were collected during 4 separate periods. Five kangaroos were included in each sampling period, with 4 receiving either IM or PO meloxicam and 1 receiving IV meloxicam. In this way, the IM group, along with 2 IV kangaroos, were fully sampled over 2 sampling periods and likewise for the PO group with the 2 remaining IV kangaroos. Manual restraint for examinations and each sample collection was performed as described above. Plasma samples were collected at time (t) = 0, 0.5, 1, 2, 4, 6, 8, 12, and 48 hours for the PO kangaroos and at t = 0, 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 48 hours for the IM and IV kangaroos. Sampling was conducted in a staggered fashion such that no kangaroo was sampled at consecutive time points. Each kangaroo was sampled at every other time point for a total of 5 or 6 samples from each individual during a sampling period (eg, t = 0, 1, 4, 8, and 24 hours or t = 0.5, 2, 6, 12, and 48 hours). This yielded 4 samples per time point, which were used to build the population data pharmacokinetic curves, ie, sparse sampling method.
Blood samples were collected using a 22-gauge, 1-inch needle on a 3-mL luer-lock syringe from the lateral saphenous vein or the lateral coccygeal vein and placed immediately in lithium heparin blood collection tubes (BD Microtainer Tube with BD Microgard Closure with Lithium Heparin Additive; BD Biosciences). Samples were kept in a cooler with ice packs until centrifuged for 10 minutes at 3,000 rpm. Centrifuged plasma was pipetted into cryovials (Fisherbrand Externally Threaded Cryogenic Storage Vials; Thermo Fisher Scientific) and stored in an ultralow freezer (−80 °C) until shipment on dry ice for analysis.
Sample analysis
Analysis of meloxicam in plasma samples was conducted using a reversed-phase HPLC method previously described.17 The system consisted of a 2,695 separations module, a 2,487-UV absorbance detector, and a computer equipped with Empower software (Waters). The compounds were separated on an Xbridge C18 (4.6 X 250 mm, 5 µm) column with a 5-µm Xbridge guard column. The mobile phase was a mixture of (1) 10 mL of glacial acetic acid in 1 L of H2O (pH 3.0 adjusted with sodium hydroxide), and (2) acetonitrile (50:50). Absorbance was measured at 360 nm with a flow rate of 1 mL/min. Meloxicam was extracted from plasma samples using a liquid-liquid extraction. Previously frozen plasma samples were thawed and vortex mixed, and 100 µL of plasma was transferred to a screw top tube, and 15 µL of piroxicam (internal standard, 5 µg/mL) was added followed by 100 µL of 1 M HCl and 2 mL of chloroform. The tubes were vortexed for 60 seconds and then centrifuged for 20 minutes at 1,070 X g. The organic phase was transferred to a clean glass tube and evaporated to dryness with nitrogen. Samples were reconstituted in 250 µL of mobile phase, and 100 µL was injected into the chromatography system. Standard curves for plasma analysis were prepared by fortifying untreated plasma with meloxicam to produce a linear concentration range of 0.005 to 5 µg/mL. Calibration samples were prepared exactly as plasma samples.17 The lower limit of quantification during validation was 0.005 µg/mL. The intra- and interassay variability ranged from 1.1% to 10%, and the average recovery for meloxicam was 95%.
Pharmacokinetic analysis
Due to the pooled nature of the pharmacokinetic data, statistical analysis to compare the significance of the pharmacokinetic parameters between dosing groups was not feasible using ranked sum tests and so was not performed.
Results
Plasma concentration of meloxicam was detectable in all blood samples and used to generate the pharmacokinetic parameters presented in Table 1. Pharmacokinetic data from IV administration generated with data from 2 individuals at each time point are presented in Supplementary Table S1. The Cmax and tmax after IM administration were 1.071 μg/mL and 0.5 hours, while PO administration produced a Cmax and tmax of 0.445 μg/mL and 6 hours, respectively. Plasma concentration versus time curves are presented for the IM (Figure 1) and PO (Figure 2) groups.
Terminal half-life (t½), elimination rate constant (λz), maximum plasma concentration (Cmax), time to maximum plasma concentration (tmax), area under the plasma concentration-versus-time curve from time 0 to last point (AUC0–last), area under the plasma concentration-versus-time curve from time 0 to infinity (AUC0–∞), absolute bioavailability (F), and apparent volume of distribution after extravascular administration (V/F) are presented from red kangaroos (Osphranter rufus) administered either a single IM or PO dose of meloxicam.
| Pharmacokinetic parameter | IM | PO |
|---|---|---|
| t½ (h) | 13.03 | 9.90 |
| λz (1/h) | 0.05 | 0.07 |
| tmax (h) | 0.5 | 6 |
| Cmax (µg/mL) | 1.071 | 0.445 |
| AUC0–last (h·µg/mL) | 11.64 | 6.66 |
| AUC0–∞ (h·µg/mL) | 12.46 | 7.02 |
| F | 129% | 73% |
| V/F (mL/kg) | 234 | 557 |
Mean ± SD plasma concentrations of meloxicam sampled and pooled from 8 red kangaroos (Osphranter rufus) following IM administration of 1 dose at 0.2 mg/kg. Confidence bars and population data at each time point represent data from 4 individuals.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.24.10.0326
Mean ± SD plasma concentrations of meloxicam sampled and pooled from 8 red kangaroos (O rufus) following oral administration of 1 dose at 0.2 mg/kg. Confidence bars and population data at each time point represent data from 4 individuals.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.24.10.0326
Mortality event
One study individual, an 11.5-year-old intact female, weighing 31.8 kg, collapsed approximately 15 minutes after receiving an IV dose of meloxicam. Assessment of this animal revealed bradycardia and fixed and dilated pupils with no corneal reflex. This kangaroo was immediately transported to the facility’s veterinary clinic where resuscitation measures were attempted but unsuccessful. Gross necropsy revealed marked hemorrhage within the cranium, causing displacement of the right cerebral hemisphere (Figure 3). No further signs of trauma to the skin, skull, or brain were present. Tissues were sampled and placed in 10% neutral buffered formalin for histopathologic evaluation by a veterinary pathologist. The histopathology findings included acute congestion, hemorrhage, and edema within the meninges of the brain. Mild arteriosclerosis of the aorta and heart was also identified. No adverse effects were noted in any of the other kangaroos throughout the course of this study.
A view of the right side of the cranium with the brain removed (left) and a dorsal image (right) with the brain still within the cranium of a red kangaroo (O rufus) skull following gross necropsy. This individual collapsed and died approximately 15 minutes after receiving a dose of meloxicam IV. Note the right-sided intracranial hemorrhage.
Citation: American Journal of Veterinary Research 86, 6; 10.2460/ajvr.24.10.0326
Discussion
To the authors’ knowledge, this is the first study examining the pharmacokinetics of meloxicam in any macropod species and extralabel drug use complied with provisions of AMDUCA and 21 CFR §530. Our findings revealed that IM meloxicam dosed at 0.2 mg/kg reached higher Cmax and had a longer t1/2 than when dosed PO. Additionally, the Cmax achieved via IM dosing (1.071 μg/mL) is similar to the range of plasma concentrations determined to be therapeutically efficacious in other species (0.2 to 0.93 μg/mL)18–21 and remained above 0.2 μg/mL for approximately 20 hours. The Cmax for PO-dosed meloxicam (0.445 μg/mL) also fell within the range previously mentioned and maintained plasma concentrations within this range for approximately 12 hours. While IM dosing yields higher plasma concentrations of meloxicam and has a longer t1/2 compared to PO dosing, it may be impractical for clinicians treating kangaroos if those patients are not acclimated to human handling such that an injection may be administered. This makes PO dosing an attractive alternative and an area for future study.
Meloxicam plasma concentrations in the kangaroos dosed PO were likely affected by the kangaroo gastrointestinal system. Although not true ruminants, red kangaroos are primarily foregut fermenting animals.15 Tajima et al22 discussed the challenges of PO dosing in ruminants which include large stomach volumes that dilute the drug, slow gastric emptying into the intestines, and the potential for gut flora to metabolize or inactivate drug in the stomach. In addition, recommended PO doses of meloxicam in cattle are higher than those for injectable meloxicam (1 vs 0.5 mg/kg, respectively) due to the perceived first-pass effect.23 In dogs, horses, and preruminant calves, PO meloxicam bioavailability approaches 100%,21,24,25 but in mid lactation dairy cows, this number was just 87.2%.26 The kangaroos in this study exhibited oral bioavailability (73%) closest to that of goats (79%), llamas (76%), and sheep (72%)27–29 and greater oral bioavailability than in hindgut fermenters guinea pigs (54%) and koalas (negligible).6,8 The decreased bioavailability in the PO group in this study yielded a large decrease in Cmax and AUC compared to those same values in the IM group.
The t1/2 was shorter for the PO group than the IM group at 9.9 hours and 13.03 hours, respectively. This contrasts with findings in guinea pigs, where these values were approximately the same at 3.5 ± 1.1 hours and 3.7 ± 0.7 hours after PO and IV administration, respectively,8 and in calves where the t1/2 was longer when dosed PO (mean, 27.54 hours) vs after IV administration (mean: 20.35 hours).30 The t1/2 determined for red kangaroos in this study was also shorter than those seen in PO-dosed sheep (15.4 hours)29 and llamas (22.7 hours),28 which is interesting given the similarities in oral bioavailability compared to sheep and llamas discussed above. For the kangaroos in the present study, the shorter t1/2 for PO meloxicam could be due to the higher volume of distribution of meloxicam when dosed PO and may indicate decreased plasma protein binding when dosing meloxicam PO and/or increased tissue binding of the drug before reaching steady-state pharmacokinetics; however, investigation of these factors is beyond the scope of the present study. This may mean that to maintain a therapeutic effect over an entire day, an PO loading dose may be required. However, multidose pharmacokinetic and pharmacodynamic studies and safety studies are necessary to determine steady-state and therapeutic meloxicam plasma concentrations before formal dosing recommendations can be made.
In zoological medicine, it is common practice to extrapolate drug dosages from closely related species when no published data are available for a species of interest. In the case of red kangaroos, the closest phylogenetic relative with any published data regarding meloxicam is the koala,6 but there are stark differences in the pharmacokinetics of meloxicam in these 2 species. Whereas the kangaroos in this study were able to absorb and maintain substantial plasma concentrations of meloxicam both PO and parenterally, koalas administered meloxicam PO at a dose of 0.2 mg/kg rapidly cleared or struggled to absorb the drug as evidenced by median t1/2 of 1.19 hours (range, 0.71 to 1.62 hours) and Cmax of 0.013 μg/mL. There are anatomic and physiologic explanations for these differences. While kangaroos are primarily foregut fermenting grazers, koalas are hindgut fermenting arboreal folivores that consume and metabolize, normally toxic, Eucalyptus foliage.15,31 Some of the koala’s adaptations that allow them to safely digest these plants include extensive upregulation of cytochrome enzymes that are suspected to be responsible for the rapid clearance of meloxicam.32,33 This reinforces the need for species-specific pharmacologic studies in zoological medicine, even among closely related mammalian genera.
The individual kangaroo that died during this study was of advanced age and was determined via histopathologic evaluation to be suffering from undiagnosed cardiovascular disease. Nonselective cyclooxygenase-2 inhibitors are known to inhibit platelet function through the inhibition of thromboxane A2, prostacyclin, and other prostaglandins.34,35 This inhibition of platelet function may increase the risk of hemorrhage, including hemorrhagic stroke; however, the evidence in the human literature is conflicting with some studies36,37 finding no increased risk, while other studies38,39 found mildly increased risk of hemorrhage, particularly when meloxicam is dosed parenterally. One study40 identified a markedly increased rate of subdural and subarachnoid hemorrhage in juvenile swine administered meloxicam and then exposed to sudden rotational movement of the head when compared to buprenorphine. Otherwise, there is scant information regarding the increased risk of intracranial hemorrhage after NSAID administration in the veterinary literature. While it was beyond the scope of this study to examine the relationship between meloxicam administration and the risk of intracranial hemorrhage, the underlying cardiovascular disease in the affected kangaroo may have played a larger role in the mortality event than the meloxicam itself. Additionally, although this individual was well acclimated to handling, and only exhibited mild signs of stress while being handled, it cannot be ruled out that these handling events caused spikes in blood pressure that also contributed to the cerebrovascular event. At the moment of the event, it was noticed that this animal was hopping and then suddenly appeared to slip before hitting the floor. It is possible, that the animal slipped on the floor, leading to a fall that caused sudden inertial forces to be exerted on the head that also contributed to the hemorrhage, like the juvenile swine study mentioned above. Although anecdotal, Zoological Information Management System drug usage data records indicate no adverse effects with IV meloxicam administration from 6 recorded instances nor any following IM or SC administration following 287 and 475 administrations, respectively.16 However, without any kangaroo-specific safety studies, it is possible that a combination of the underlying cardiovascular disease, meloxicam administration, and other factors yielded a compounded increased risk. It is additionally possible that kangaroos may be more sensitive to the antiplatelet effects of NSAIDs compared to humans and other animals, but definitive investigation is warranted.
In performing this study, the ability to safely and consistently handle and manually restrain these animals was critical to its success. The red kangaroo mob used in this study is maintained with outdoor daytime access in a large yard that is open as a walk-through exhibit for guests who are permitted to interact with the animals. In addition, this entire mob is socially reared and handled routinely by the animal care staff. This consistent habituation to human presence, touch, and restraint is what allowed for the repeated handling of these kangaroos with minimal stress to facilitate sample collection. Without this relationship between the veterinary team, keepers, and kangaroos, this study would not have been possible. Although these kangaroos were acclimated to people, mild to moderate stress responses were observed in some individuals being used for this study, and their stress responses could yield a limitation to interpreting results.41 Additional limitations included the small sample size and staggered sampling rather than sampling at each time point from each individual and building individual pharmacokinetic profiles.
This study established the pharmacokinetic parameters of meloxicam in red kangaroos following a single IM or PO dose. The findings indicate that meloxicam reaches plasma concentrations known to be efficacious in other animals when given IM and may reach these levels when administered PO. Additionally, the shorter t1/2 and lower AUC observed with PO dosing compared to IM dosing suggest that the complex kangaroo gastrointestinal tract exerts effects on meloxicam pharmacokinetics. While there was 1 animal that died during the study due to intracranial hemorrhage, it is unclear if IV meloxicam administration in that animal contributed to the cause of death, as data in humans are conflicting. Future investigations into the pharmacodynamics, safety, and multidose effects of meloxicam in red kangaroos are needed to fully establish appropriate dosing recommendations. In addition, investigating the effects of meloxicam on platelets and coagulation in red kangaroos would be beneficial toward understanding if this species is more susceptible than other taxa to NSAID-induced hemorrhage.
Supplementary Materials
Supplementary materials are posted online at the journal website: avmajournals.avma.org.
Acknowledgments
The authors thank the contact area animal care staff at Nashville Zoo for their time, effort, and patience with this study, including Megan Cohn, Daniel Brandt, Abbe Aiello, Allison Weindorf, Bryce Barry, Dakota Sullivan, Dori Lynn Coburn, Katrina Camaiore, Kelly Wisner, Laurel Smith, Michael Smith, Paxton Hensley, and Zack Seymour. We thank Belmont University for providing funds that supported this project.
Disclosures
The authors have nothing to disclose. No AI-assisted technologies were used in the composition of this manuscript.
Funding
Funds from Belmont University were provided that supported this project.
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