• View in gallery

    Mean plasma meloxicam concentrations in lesser flamingos (Phoeniconaias minor) over time after oral (squares) or IM (circles) administration of a single dose of meloxicam (0.5 mg/kg) at 0 hours. Error bars represent SD. Blood samples were collected from flamingos at 3 (n = 13 birds), 2 (2), or 1 (1) selected point after administration. Each data point represents 4 birds.

  • View in gallery

    Plasma meloxicam concentrations (circles) over time in the individual flamingos represented in Figure 1 after IM administration of the drug. Lines were fitted by use of 1-compartment modeling to individual birds (A) and by means of a population pharmacokinetics approach and NLME modeling to account for interindividual (between-subject) variability (B).

  • View in gallery

    Plasma meloxicam concentrations (circles) in the individual flamingos represented in Figure 1 after oral administration of the drug. Lines were fitted by use of 1-compartment modeling to individual birds (A) and by means of a population pharmacokinetics approach and NLME modeling to account for interindividual (between-subject) variability (B). Notice the improvement in fit when the variability were accounted for through the population approach.

  • View in gallery

    Semilogarithmic values for plasma meloxicam concentrations (circles) in the individual flamingos represented in Figure 1 after oral (A) and IM (B) administration of the drug. Lines were fitted by use of NLME modeling to account for interindividual (between-subject) variability.

  • 1. Brown C, King CE, Mossbarger S, et al. Flamingo taxon advisory group husbandry manual. Available at: aviansag.org/Husbandry/Unlocked/Care_Manuals/Flamingo%20Husbandry%20Guidelines.pdf. Accessed Jul 15, 2015.

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  • 11. 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: 18.

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  • 14. Molter CM, Cole GA, Gagnon DJ, et al. Pharmacokinetics of meloxicam after intravenous, intramuscular, and oral administration of a single dose to Hispaniolan Amazon parrots (Amazona ventralis). Am J Vet Res 2013; 74: 375380.

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  • 15. Lacasse C, Gamble KC, Boothe DM. Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus). J Avian Med Surg 2013; 27: 204210.

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  • 16. 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: 2533.

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  • 17. Naidoo V, Wolter K, Cromarty AD, et al. The pharmacokinetics of meloxicam in vultures. J Vet Pharmacol Ther 2008; 31: 128134.

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  • 24. Simeone CA, Nollens HH, Meegan JM, et al. Pharmacokinetics of single dose oral meloxicam in bottlenose dolphins (Tursiops truncatus). J Zoo Wildl Med 2014; 45: 594599.

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  • 25. US Pharmacopeia. USP37-NF32. (1225) Validation of compendial procedures. Rockville, MD: US Pharmacopeial Convention, 2014.

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Population pharmacokinetics of a single dose of meloxicam after oral and intramuscular administration to captive lesser flamingos (Phoeniconaias minor)

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  • 1 Latin American Association of Zoological Parks and Aquariums (ALPZA), Nstra sra del Rosario 165, Las Condes, Santiago, Chile 7560758.
  • | 2 Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27607.
  • | 3 Veterinary Services, Fort Worth Zoo, 1989 Colonial Pkwy, Fort Worth, TX 76109.
  • | 4 Animal Program, Fort Worth Zoo, 1989 Colonial Pkwy, Fort Worth, TX 76109.
  • | 5 Veterinary Services, Fort Worth Zoo, 1989 Colonial Pkwy, Fort Worth, TX 76109.

Abstract

OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach.

ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age.

PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography.

RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours.

CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

Abstract

OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach.

ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age.

PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography.

RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours.

CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

Information is limited on the pharmacokinetics of NSAIDs in birds. In captivity, avian species are probably more likely to have had trauma than are other species, making the use of anti-inflammatory drugs a common component of treatment plans. This is particularly true for institutions receiving or holding large populations of birds, such as rehabilitation centers and zoos.

Leg fractures are the most common cause of morbidity and death in captive flamingos. Such fractures usually occur when the birds are startled or physically restrained or when they attempt to stand prematurely while still recovering from anesthesia.1 Fractures of the tarsometatarsus and the proximal aspect of the tibiotarsus are the most common types in adult birds.1 A retrospective review2 of necropsy reports for captive greater flamingos at Zoo Basel in Switzerland revealed a trauma prevalence of 28% between 1972 and 2012 (n = 124). Foot lesions and other pathological changes to feet of flamingo species in captivity have been described extensively.3,4

Management of trauma and foot problems in flamingos requires analgesics and anti-inflammatory medications. Nonsteroidal anti-inflammatory drugs are among the most common drugs used to alleviate pain in birds.5 Meloxicam is a commonly prescribed NSAID for companion and zoo birds, and commercially available formulations allow use of appropriate volumes for oral, IV, and IM administration. An oxicam derivative, meloxicam is believed to preferentially inhibit cyclooxygenase-2 in mammalian species. Mechanisms of action, roles in treating pain and inflammation, and adverse effects of NSAIDs are reported elsewhere.6 Adverse effects in birds vary by species, drug, dose, and administration frequency.7–11 To the authors' knowledge, no studies have been performed to investigate potential toxic effects of meloxicam in any flamingo species; however, given the mechanism of action of the drug (inhibition of renal prostaglandin synthesis), the main adverse effects are expected to impact renal tissue and function.

Empirically derived doses of meloxicam for administration to avian species range between 0.1 and 2 mg/kg.5 Results of pharmacokinetic, analgesic, and toxicologic analyses of meloxicam are available for several avian species,7,8,10–18 showing wide interspecies variability in pharmacokinetic properties and suggesting the need to evaluate pharmacokinetics in each species before dosage recommendations can be made. To the authors' knowledge, no data have been reported regarding pharmacokinetic values for any anti-inflammatory drugs administered to any Phoenicopteriformes species.

The variability and source of variability among pharmacokinetic values reported for different avian species could be caused by species differences in the degree of protein binding or drug biotransformation but may also be attributable in part to study design. Because collection of blood samples from avian species can be challenging owing to the distress and blood loss associated with collection, studies have been limited to including small numbers of subjects and collected samples. Therefore, a protocol for collection of a minimal number of samples (sparse sampling) and NLME modeling that was originally designed for humans19 may be useful for birds.

Blood samples cannot be collected from some exotic and zoo animals, such as captive birds, as frequently as from large domestic animals in which traditional standard 2-stage pharmacokinetic methods are used. The sparse sampling strategy was designed to enable blood samples to be collected from each animal in a group as infrequently as possible, ensuring that samples from 4 animals were collected per assessment point between 0 and 13 hours after drug administration. These methods have been successfully used by our laboratory group for studies20–23 involving sparse sampling of zoo and exotic species. This approach allows for sparse sampling (eg, 1 to 3 samples/subject) and mixed-effects modeling to estimate the fixed effects (depicting pharmacokinetic parameters) and random effects (to account for interindividual variation). The models derived from this approach allow assessment of the magnitude and source of the variability in a study. The purpose of the study reported here was to use a similar population pharmacokinetics approach to determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor).

Materials and Methods

Animals

Sixteen hand-raised lesser flamingos (11 males and 5 females) between 1 and 4 years of age (median, 1.5 years) were used in the study. Mean ± SD body weight was 1,472 ± 247 g (median, 1,385 g; range, 1,210 to 2,060 g). All flamingos had been hatched at the Fort Worth Zoo in Fort Worth, Tex. Twelve days prior to the start of the study, a complete physical examination had been performed, and results were unremarkable. Blood samples had also been collected via the right jugular vein by use of a 25-gauge needle and 3-mL syringe for performance of a CBC and serum biochemical analysis. Results of hematologic tests were compared with reported physiologic values for the species,a and no clinically important abnormalities were identified. An additional 0.55 mL of blood was collected from each flamingo prior to drug administration for preparation of blank plasma samples for pharmacological testing.

During the study, all 16 flamingos were housed together in a holding room measuring 4.3 × 3.0 × 2.4 m (length × width × height). The substrate the flamingos were housed on was made of 70% concrete and 30% red clay.

The concrete flooring sloped to a shallow (15.2-cm-deep) pool. Walls were made of concrete block, and the ceiling was made of painted and sealed wood. Two 0.6 × 0.6-m open windows and a screen door were also present. Humidity and temperature of the holding room were not controlled at the time of the study. Flamingos were provided a commercial flamingo feedb in black rubber tubs with fresh water; the tubs were emptied, disinfected, and refilled daily throughout the study. Food was not withheld before or after sample collection began, and routine husbandry practices were used throughout the study. The study protocol was approved by the Institutional Animal Care and Use Committee of Fort Worth Zoo.

Study design

A population-based sample collection scheme20,21,23 was used to collect representative samples while minimizing distress and blood loss from the flamingos. A single dose of meloxicamc (0.5 mg/kg) was administrated IM (right side of pectoral muscles) to each of the 16 flamingos. Blood samples were collected from 4 flamingos via the right jugular vein by use of a 25-gauge needle and 3-mL syringe or, occasionally, via a tarsal vein with a 25-gauge needle and 1-mL syringe at each of the following points: 5, 30, and 45 minutes and 1, 1.5, 2, 4, 6, 8, 10, and 13 hours after meloxicam administration. Samples were collected 3 times from 13 birds, from 2 birds twice, and from 1 bird only once on the basis of an established collection protocol (Appendix 1). After a 15-day washout period, a single dose of meloxicamd (0.5 mg/kg) was again administered to the flamingos, but this time orally into the esophagus via a 20-mm red rubber feeding tube and syringe. Blood samples were collected from 4 flamingos at each point following the same protocol as for IM administration; however, the number of sample collection points for individual birds was different (Appendix 2). All blood samples were centrifuged at 959 × g for 5 minutes, and plasma was harvested, aliquoted, and stored at −80°C until shipment to North Carolina State University College of Veterinary Medicine for drug analysis and pharmacokinetic evaluation.

Measurement of plasma meloxicam concentrations

Thawed plasma samples were analyzed by HPLC. The HPLC system consisted of a quaternary solvent delivery system (flow rate, 1 mL/min), an autosampler,e and a UV detectorf set at a wavelength of 279 nm. Chromatograms were integrated with a computer program.g The reverse-phase C8 columnh was kept at a constant temperature of 40°C. The mobile phase for HPLC analysis consisted of 40% acetonitrile, and 60% 0.05M sodium acetate buffer. Glacial acetic acid was added to the buffer to adjust the pH to between 3.7 and 3.8. Fresh mobile phase was prepared, filtered (0.45 μm), and degassed for each day's run.

The assay method used was similar to that in previous studies23,24 but was validated specifically for this study by fortifying the blank plasma samples collected before the flamingos received meloxicam. The reference standard of meloxicami was used to prepare a stock solution that was used to fortify blank sample matrix. The meloxicam calibration curve consisted of 8 standard solutions that ranged between 0.01 and 10 μg of reference standard/mL and included a blank (0 μg/mL) sample. The blank sample was used to detect interfering peaks that eluted into the window of the chromatographic peak of interest and to measure the degree of background interference. The calibration curve was accepted when the linear coefficient of determination (R2) was ≥ 0.99 and when the calibration curve concentrations could be reverse-calculated to within 15% of the true concentration of the standard. Fresh calibration curves were prepared for each day's analysis. The accuracy of the assay was within 6.2% of the nominal concentration of fortified samples.

Retention time for the peak of interest was approximately 4.9 to 5.0 minutes. Limit of quantification for meloxicam in flamingo plasma samples was 0.01 μg/mL, which was determined from the lowest point on a linear calibration curve that yielded an acceptable accuracy and within the signal-to-noise ratio as recommended by the US Pharmacopeia25 and International Conference on Harmonisation.26

Pharmacokinetic analysis

Pharmacokinetic softwarej,k was used to calculate values of pharmacokinetic parameters. Plasma meloxicam concentrations following administration by each route were first plotted on a graph to identify potential pharmacokinetic models for analysis.

Initial estimates of pharmacokinetic parameters were obtained by use of naïve pooled plasma samples for which a pharmacokinetic model was fit to the mean concentration at each assessment point. This model was used to determine the best initial estimates of primary pharmacokinetic parameters to be used for the population pharmacokinetics approach. Population pharmacokinetic analysis was performed by fitting the concentrations to a model by use of an NLME approach.l Primary pharmacokinetic parameters for the population were considered fixed effects and the interindividual (between-subject) variability was modeled as a random effect. Remaining differences between predicted concentrations and measurements were accounted for by residual errors (within-subject variation).

The model was parameterized through compartmental analysis of the data in a 1-compartment approach with first-order absorption after IM and oral administration as indicated by the following formula (equation 1):

D1

where t is time, K01 is the absorption rate (assuming first-order absorption), K10 is the elimination rate constant, V is the apparent volume of distribution, and D is the dose. Secondary parameters calculated from the model included Cmax, time to Cmax, AUC, and the half-lives corresponding to K01 and K10. Models were run with the quasirandom parametric expectation maximization engine. Final models were selected on the basis of goodness-of-fit plots, the significance of differences between models in values for twice the negative logarithmic likelihood, values of the Akaike information criterion (which adjusted for the number of parameters [degrees of freedom] in the fit), and coefficient of variation in parameter estimates. Inter-individual (between-subject) variability (variance of a given parameter among subjects) was calculated by use of an exponential error model as follows (equation 2):

D2

where Pi is the pharmacokinetic parameter of interest for individual i, θ P is the typical value (fixed effect) of the population estimate of the parameter of interest, and ηiP is the random effect for the interindividual (between-subject) differences for the parameter of interest. The η values were assumed to be independent and have a logarithmically normal distribution with a mean of 0 and variance of ω2. A multiplicative model was used to describe the residual random variability (ϵ) of the data for once-daily administration, where ϵ represented the residual intrasubject (within-subject) variability with a mean of 0 and variance of σ2 as follows (equation 3):

D3

where Cobs is the observed concentration for the individual and Cpred is the model-predicted concentration plus the error value (ϵ).

Results

Plasma drug concentration profiles were established for meloxicam administered PO and IM to lesser flamingos at a dose of 0.5 mg/kg (Figure 1). Plasma concentrations after IM administration reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL (Table 1). Mean AUC was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean AUC was 22.16 ± 717 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours.

Figure 1—
Figure 1—

Mean plasma meloxicam concentrations in lesser flamingos (Phoeniconaias minor) over time after oral (squares) or IM (circles) administration of a single dose of meloxicam (0.5 mg/kg) at 0 hours. Error bars represent SD. Blood samples were collected from flamingos at 3 (n = 13 birds), 2 (2), or 1 (1) selected point after administration. Each data point represents 4 birds.

Citation: American Journal of Veterinary Research 77, 12; 10.2460/ajvr.77.12.1311

Table 1—

Values of pharmacokinetic parameters obtained by means of a population pharmacokinetics approach and NLME modeling for a single dose of meloxicam (0.5 mg/kg) administered IM or PO to lesser flamingos (Phoeniconaias minor; n = 16*).

 IMPO
VariableEstimateSDCV (%)EstimateSDCV (%)
θ Ka (1/h)25.05163.64653.250.710.3854.29
θ V (L/kg)0.080.0226.980.200.0735.64
θ Ke (1/h)0.360.0616.680.110.0758.35
Tmax (h)0.170.88511.453.070.8126.36
AUC (μg•h/mL)17.782.7915.6622.167.1732.36
Cmax (μg/mL)6.013.3856.141.790.3318.32
Cl (L/kg/h)0.030.0015.660.020.0132.36
Ka t1/2 (h)0.030.18653.240.980.5354.29
Ke t1/2 (h)1.930.3216.686.053.5358.35

Blood samples were collected from flamingos at 3 (n = 13 birds), 2 (2), or 1 (1) randomly selected point after administration with samples collected from 4 birds at each point.

Cl = Clearance. CV = Coefficient of variation. Ka t1/2 = Absorption half-life. Ke t1/2 = Elimination half-life. Tmax = Time to Cmax. θ Ka = θ (typical value) for the absorption rate constant. θ Ke = θ for the elimination rate constant. θ V = θ for apparent volume of distribution.

Concentration-versus-time curves for both routes of administration were fitted for individual flamingos and by use of NLME modeling, revealing an improvement in curve fit by including the random effect to account for interindividual variation with the population pharmacokinetics approach (Figures 2–4).

Figure 2—
Figure 2—

Plasma meloxicam concentrations (circles) over time in the individual flamingos represented in Figure 1 after IM administration of the drug. Lines were fitted by use of 1-compartment modeling to individual birds (A) and by means of a population pharmacokinetics approach and NLME modeling to account for interindividual (between-subject) variability (B).

Citation: American Journal of Veterinary Research 77, 12; 10.2460/ajvr.77.12.1311

Figure 3—
Figure 3—

Plasma meloxicam concentrations (circles) in the individual flamingos represented in Figure 1 after oral administration of the drug. Lines were fitted by use of 1-compartment modeling to individual birds (A) and by means of a population pharmacokinetics approach and NLME modeling to account for interindividual (between-subject) variability (B). Notice the improvement in fit when the variability were accounted for through the population approach.

Citation: American Journal of Veterinary Research 77, 12; 10.2460/ajvr.77.12.1311

Figure 4—
Figure 4—

Semilogarithmic values for plasma meloxicam concentrations (circles) in the individual flamingos represented in Figure 1 after oral (A) and IM (B) administration of the drug. Lines were fitted by use of NLME modeling to account for interindividual (between-subject) variability.

Citation: American Journal of Veterinary Research 77, 12; 10.2460/ajvr.77.12.1311

Discussion

The study design and analysis method used in the present study to evaluate the pharmacokinetics of meloxicam in lesser flamingos was successful because the population pharmacokinetics approach (with NLME modeling) allowed estimation of θ, the typical value for population pharmacokinetics values in the study (fixed effects), and η, the interindividual (between-subject) variation in the population (random effects). A sparse sampling strategy was used, involving 4 flamingos at each predetermined point of blood sample collection, allowing minimization of distress to and blood loss from the birds. The challenges of blood sample collection from many zoo or exotic species make this an ideal approach to obtaining pharmacokinetic estimates when conditions preclude performance of traditional 2-stage analysis (by which samples are collected more frequently from individual animals).

Inclusion of the parameter η (inter-individual [between-subject] variability) in the NLME model provided an improvement in the AUC over that achieved with traditional pharmacokinetic modeling. Variation among flamingos in some pharmacokinetic data remained large, and NLME modeling alone could not identify the source of this observed variation. Although NLME modeling allows examination of covariate factors that may have been responsible for this variability, as has been reported elsewhere,19 there were no obvious covariates to be examined in the present study.

Pharmacokinetic data in the present study indicated a longer half-life of meloxicam following oral (> 6 hours) versus IM (approx 2 hours) administration. Whether this represented a real difference or simply a high degree of variation could not be determined. Intramuscular administration resulted in greater variability in absorption rate and absorption half-life, and the time to Cmax was greater than with oral administration, which was not unexpected (Figure 1 and Table 1). Values of other parameters were less variable. Oral administration resulted in a larger AUC than did IM administration, with the ratio of the AUC for oral administration to the AUC for IM administration equal to approximately 125%. The larger AUC was most likely caused by a longer half-life rather than higher absolute bioavailability. Oral administration also resulted in high variability among flamingos in Cmax values (Figure 3), which was not unexpected for drugs administered into the stomach of birds. Despite this variability, oral administration resulted in adequate drug exposure (as measured by AUC), compared with that following IM administration. The longer half-life of meloxicam achieved with oral administration suggested that the required administration frequency for the oral route would differ from that of the IM route, but this would need to be confirmed with additional studies.

Findings of the present study supported previous observations regarding variability among avian species in studies7,8,10–18 of the pharmacokinetic properties of meloxicam. An advantage of the present study over other studies was the use of NLME modeling and inclusion of 2 routes of administration in a crossover design. With the AUCs and elimination half-lives achieved in the present study taken into account, lesser flamingos appeared to have a higher absorption rate and slower elimination rate than has been reported for meloxicam in raptors.15 Compared with reported pharmacokinetic values for psittacines,14,18 lesser flamingos had a lower absorption rate and faster elimination rate.

Insufficient information exists regarding the plasma meloxicam concentration capable of providing analgesia in birds. To the authors' knowledge, only 1 study13 has been conducted to investigate the analgesic effect of meloxicam in birds, in which a dose of 1 mg/kg, IM, was considered adequate to provide relief of arthritic pain in Hispaniolan Amazon parrots. For those parrots, a mean ± SD plasma meloxicam concentration of 35 ± 2.2 μg/mL14 was considered an ideal target to provide sufficient analgesia. Although the present study was not designed to evaluate effectiveness of meloxicam for providing analgesia, the 0.5 mg/kg dose when administered IM was able to achieve that therapeutic plasma concentration (mean ± SE Cmax, 6.01 ± 3.38 μg/mL) but this same dose when administered PO reached only the lower limit of the therapeutic range, with a mean Cmax of 1.79 ± 0.33 μg/mL. Additional research is needed to determine whether plasma meloxicam concentrations sufficient to provide analgesia in Hispaniolan Amazon parrots have a similar effect in flamingo species.

Although no studies of adverse effects of NSAID administration to flamingos have been reported, meloxicam administered orally to Hispaniolan Amazon parrots at a dose of 1.6 mg/kg every 12 hours for 15 days resulted in no apparent adverse effects in renal, gastrointestinal, or hemostatic variables in 1 study10 Nevertheless, and given the interspecies variability in the pharmacokinetics of meloxicam, caution is advised when administering or evaluating higher doses of this drug in flamingos.

Results of the study reported here suggested that for oral administration of meloxicam to lesser flamingos, a dose > 0.5 mg/kg could be required to reach a therapeutic concentration. The half-life of the drug after IM injection was shorter than after oral administration. However, without additional study, it is not known whether this would translate to a need for more frequent IM administration in a clinical setting. The frequency of administration is not necessarily associated with the plasma concentration half-life because tissue NSAID concentrations can persist longer than plasma NSAID concentrations.27

Acknowledgments

Supported by Fort Worth Zoo.

The authors thank Delta Dise for assistance with sample analysis.

ABBREVIATIONS

AUC

Area under the concentration-versus-time curve

Cmax

Maximum plasma concentration

HPLC

High-performance liquid chromatography

NLME

Nonlinear mixed effects

Footnotes

a.

ISIS physiological reference intervals for captive wildlife [CD-ROM]. Bloomington, MN: International Species Information System, 2002.

b.

Mazuri flamingo complete diet, Mazuri PMI Nutrition International, St Louis, Mo.

c.

Metacam solution for injection, Boehringer Ingelheim Vetmedica Inc, Saint Joseph, Mo.

d.

Metacam oral suspension, Boehringer Ingelheim Vetmedica Inc, Saint Joseph, Mo.

e.

Agilent 1200 series solvent delivery system, Agilent Technologies, Wilmington, Del.

f.

Agilent 1200 series variable wavelength detector, Agilent Technologies, Wilmington, Del.

g.

Agilent OpenLAB software, Agilent Technologies, Wilmington, Del.

h.

Zorbax Rx-C18 (4.6 mm × 15 cm), MAC-MOD Analytical Inc, Chadds Ford, Pa.

i.

Meloxicam analytical reference standard, US Pharmacopeial Convention, Rockville, Md.

j.

WinNonlin, version 1.3, Pharsight Corp, St Louis, Mo.

k.

Phoenix NLME software, version 6.4.0.768, Certara, St Louis, Mo.

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Appendix 1

Times of blood sample collection after IM administration of a single dose of meloxicam (0.5 mg/kg) to 16 lesser flamingos (Phoeniconaias minor) in a population pharmacokinetics approach to estimation of pharmacokinetic values

Bird5 minutes30 minutes45 minutes1 hour1.5 hours2 hours4 hours6 hours8 hours10 hours13 hours
1XXX
2XXX
3XXX
4XXX
5XXX
6XXX
7XX
8XXX
9XXX
10XXX
11XXX
12XXX
13XXX
14XXX
15XX
16X

— = Not done.

Appendix 2

Times of blood sample collection after oral administration of a single dose of meloxicam (0.5 mg/kg) to the flamingos in Appendix 1.

Bird5 minutes30 minutes 45 minutes1 hour1.5 hours2 hours4 hours6 hours8 hours10 hours13 hours 
1XXX
2X
3XX
4XXX
5XXX
6XXX
7XXX
8XXX
9XXX
10XX
11XXX
12XXX
13XXX
14XXX
15XXX
16XXX

— = Not done.

Contributor Notes

Address correspondence to Dr. Sánchez (csanchez@fortworthzoo.org).