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Pharmacokinetics of a Single Dose of Oral and Intramuscular Meloxicam in African Penguins (Spheniscus demersus).

Abstract: Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that has been used orally and intramuscularly in numerous avian species, but not studied to date, in African penguins (Spheniscus demersus). The study describes the pharmacokinetic parameters of meloxicam after oral and intramuscular administration to African penguins. Several pilot studies were conducted initially where meloxicam (1, 0.5, and 0.25 mg/kg) was given intramuscularly to 4 birds, and orally (1 mg/kg) to 2 birds. Based on pilot study results, one group of 8 penguins was given meloxicam 0.5 mg/kg intramuscularly and one group of 8 penguins was given 1 mg/kg orally. Blood samples were collected at baseline and at 11 time intervals per group after administration of meloxicam. Meloxicam time to maximum plasma concentration ([T.sub.max]), maximum concentration ([C.sub.max]), and half-life ([t.sub.1/2]) after intramuscular administration were 1.00 hour, 8.03 [micro]g/niL, and 31.87 hours, respectively, while oral administration produced a [T.sub.max], [C.sub.max], and [t.sub.1/2] of 12.00 hours, 10.84 [micro]g/ mL, and 28.59 hours, respectively. Based on plasma meloxicam concentrations found to be therapeutic in other bird species and humans, the recommended dosage and frequency for African penguins is 1 mg/kg orally every 48 hours and 0.5 mg/kg intramuscularly every 24 hours. Further studies are needed to determine the multiple-dose pharmacokinetics of meloxicam in African penguins.

Key words: pharmacokinetic, analgesia, nonsteroidal anti-inflammatory, meloxicam, avian, African penguin. Spheniscus demersus

Introduction

African penguins (Spheniscus demersus) are kept commonly in zoos and aquaria and are the most commonly held captive penguin species in North America. (1) Most of this population is managed via a Species Survival Plan (SSP) because of their endangered status. (1,2) These birds receive routine medical care but can commonly develop painful medical conditions, such as pododermatitis or traumatic wounds. Pain relief is an important aspect of their care but, to date, no pharmacokinetic data have been reported for any nonsteroidal anti-inflammatory drug (NSAID) in any penguin species. (1-5)

Meloxicam is an enolcarboxamide with preferential COX-2 inhibitory activity and is one of the most commonly used NSAIDs in veterinary medicine. (3-6) It is available in oral and parenteral formulations. (7) Meloxicam has been used in over 60 species, as reported by zoological institutions. Published studies indicate that there is a wide range of doses and dosing frequencies used, and limited species-specific pharmacokinetic studies on which to base these dosages. These studies often show extensive variation in half-life ([t.sub.1/2)] Pharmacokinetic studies of meloxicam have been conducted in chickens, ostriches (Struthio camelus), ducks (Anas platyrhynchos), turkeys (Meleagris gallopavo), pigeons OColumba livia), ring-necked parakeets (Psittacula krameri), Hispaniolan Amazon parrots (Amazona ventralis), African grey parrots (Psittacus erithacus), red-tailed hawks (Buteo jamaicensis), great horned owls (Bubo virginianus), vultures (Gyps africanus, Gyps coprotheres, Neophron pernopterus, Torgos tracheliotos), and flamingos (Phoenicopterus ruber, P ruber ruber). (8-17) Dosages calculated in these studies ranged from 0.5 to 2 mg/kg, and the duration of meloxicam detectable in the plasma ranged from <0.5 to >15 hours. In one study in Hispaniolan Amazon parrots, pharmacokinetic measurements and a well-developed arthritis model for a pharmacodynamic study were used to determine dosage; results supported a recommended dosage of 1 mg/kg IV q12h for alleviating joint pain. (17) To our knowledge, no other pharmacokinetic studies have been performed concurrently with a pharmacodynamic study. (18-20) There has been mention of renal histologic changes in budgerigars (Melopsittacus undulatus), but these changes also were reported in control groups and were not significant. (21) No adverse effects (hematologic, gastrointestinal, or renal) have been reported with meloxicam with other avian species (African grey parrots, 0.5 mg/kg IM q12h for 14 days; Japanese quail [Coturnix japonica], 2 mg/kg IM q12h for 14 days). (17,22-24) In a study in kestrels (Falco sparverius) administered meloxicam at 5, 10, and 20 mg/kg PO q12h, no evidence of renal toxicity was found as determined by results of packed cell volume, serum biochemical analysis, and gross necropsy and histopathologic findings, but an increased risk of hepatic lipidosis was found with increased dose. No association with morbidity or mortality was seen with these American kestrels at 20 times the dose reported for most other species. (25) This further illustrates that meloxicam is a safe option in a variety of avian species.

Variability between studies demonstrates that each bird species metabolizes meloxicam at different rates. Meloxicam reportedly has been used to treat penguins at numerous institutions. (2,26-28) In one report, an African penguin with discospondylitis received meloxicam at 0.3 mg/kg IM q12h and then PO for 6 weeks. (27) Another penguin with cloacolithiasis was treated with meloxicam at 0.3 mg/kg PO q24h for 7 days. (28) We have used meloxicam empirically in over 30 penguins. In this study, we examined the pharmacokinetics of a single dose of meloxicam administered orally and intramuscularly in African penguins.

Materials and Methods

Animals

A total of 22 clinically normal African penguins (11 male, 11 female), aged 3 to 9 years and with weights ranging from 2 to 4 kg, were used in this study. Six penguins were used for the pilot studies to evaluate the dosing and sampling protocol and 16 penguins for the main study. The birds were housed in their exhibit at an Association of Zoos and Aquariums-accredited facility (Ripley's Aquarium of the Smokies, Gatlinburg, TN, USA), fed a standard diet of frozen-thawed capelin with a daily multivitamin throughout the duration of the study, and cared for by aquarium staff. Each penguin was restrained for a complete physical examination and had complete blood counts and biochemical panels performed within 6 months before initiation of the study and 6 months after study completion. Blood samples were collected from the right jugular vein. (1,2,29-31) No clinically significant laboratory or physical abnormalities were observed. This study was approved by the Institutional Animal Care and Use Committee at the University of Tennessee.

Experimental design

Pilot study. Three pilot studies were performed to determine an appropriate dose and sampling protocol for the main study. In the first study, 1 mg/kg meloxicam (Metacam, Boehringer Ingelheim Vetmedica GmbH, Duluth, GA, USA) was administered IM in the pectoral muscle to 2 penguins and PO to 2 other penguins. Blood samples (0.3 mL) were collected into lithium heparin tubes before treatment (time 0) and at 0.167, 0.5, 1, 2, 4, 8, 12, 24, 48, and 72 (n = 2) hours after administration. Based on these results, a second pilot study was conducted with single penguins receiving meloxicam at either 0.5 or 0.25 mg/kg IM. Blood sample collection timing was the same as described above, with the addition of a 96-hour post-administration sampling. Blood samples were kept on ice, centrifuged for 10 minutes, and the plasma collected and stored at -80[degrees]C until analysis. Penguins were fed during the duration of the study.

Main study. Two groups of 8 penguins each were evaluated in a parallel study design. Meloxicam was administered at 0.5 mg/kg IM to 1 group and at 1 mg/kg PO to the other group. Blood samples were obtained before treatment (time 0) and at 0.167, 0.5, 1, 2, 4, 8, 12, 24, 48, 72, and 96 hours after administration and handled as described above.

Sample analysis

Analysis of meloxicam in plasma samples was conducted using reversed phase high performance liquid chromatography. (32) The system consisted of a 2695 separations module, a 2487 UV absorbance detector, and a computer equipped with Empower software (Waters Corporation, Milford, MA, USA). The compounds were separated on an Xbridge C18 (4.6 x 250 mm, 5[micro]m; Waters Corp) column with a 5 [micro]m Xbridge guard column. The mobile phase was a mixture of: (1) 10 mL glacial acetic acid in 1 L [H.sub.2]O (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 [micro]L plasma was transferred to a screw top tube, and 15 [micro]L prioxicam (internal standard, 5 [micro]g/mL) was added followed by 100 [micro]L 1 M HC1 and 2 mL chloroform. The tubes were vortexed for 60 seconds and then centrifuged for 20 minutes at 1070 g. The organic phase was transferred to a clean glass tube and evaporated to dryness with nitrogen. Samples were reconstituted in 250 [micro]L mobile phase, and 100 [micro]L of this mixture was injected into the chromatography system.

Standard curves for plasma analysis were prepared by fortifying untreated plasma from African penguins with meloxicam to produce a linear concentration range of 5 to 10 000 ng/mL. The final concentrations for the calibration standard curve were 5, 10, 25, 50, 100, 250, 500, 800, 1000, 2500, 5000 and 10 000 ng/mL with quality control standards of 15, 750, 1250, 3000 and 7500 ng/mL. Calibration samples were prepared exactly as plasma samples. The lower limit of quantification during validation was 5 ng/mL. The intra- and interassay variability ranged from 1.1% to 10%, the average recovery for meloxicam was 95%.

Pharmacokinetic analysis

Individual and population pharmacokinetic parameters were estimated by using a noncompartmental approach, as implemented with Phoenix 6.3 (Certara LP, Princeton, NJ, USA). Statistical analysis was done using a t test for log-transformed data, using R-Studio running R v.3.3.1 (RStudio, Boston, MA, USA).

Results

Meloxicam administration to each penguin was performed uneventfully. All penguins remained clinically normal throughout the duration of the unfasted study. No adverse clinical effects or clinically important abnormalities on hematologic analysis and plasma biochemical panels were noted during annual physical examinations within 6 months after study conclusion.

Meloxicam [t.sub.1/2] values for the pilot studies and main study were very long compared to those of other species and similar between both forms of administration (Table 1). The [t.sub.1/2] values were not statistically different between routes. When adjusted by dose, peak concentration values were 54% greater for the IM maximum concentration ([C.sub.max]) than the PO [C.sub.max] and significantly different (P < .05). Peak concentration values also were more variable in the orally administered group (coefficient of variation [CV], 46%) than the intramuscularly administered group (CV, 23%). When adjusted by dose, the area under the curve (AUC) between times 0 and 96 hours and between times 0 and infinity were very similar between both methods of administration and their differences were not statistically significant. No significant differences were found between the other parameters in the study, namely, volume of distribution, clearance (both adjusted by bioavailability), or mean residence times.

Visual exploration of the concentration-time curves after a single dose indicated a dose of 0.5 mg/kg IM results in concentrations above the target (3.45 [micro]g/mL, the therapeutic plasma level in Hispaniolan Amazon parrots) for approximately 24 hours, while for a dose of 1 mg/kg PO, the concentrations remain above the target for approximately 60 hours (Figs 1 and 2). (16,17)

Discussion

In this study we examined the pharmacokinetics of single doses of intramuscular and oral meloxicam in African penguins. Recommendations based on a pharmacodynamic study in Hispaniolan Amazon parrots were used to determine meloxicam plasma concentrations in this study. Results of pharmacokinetic data obtained in this study suggested a dosage of 0.5 mg/kg IM q24h and 1 mg/kg PO q48h for treating painful conditions in African penguins. Further research is needed to explore repeat dosing and analgesic effects.

Meloxicam has a long [t.sub.1/2] in African penguins when compared to other studied species. (8) (14,16,18,33) In penguins, the [t.sub.1/2] is 31.87 hours after IM administration and 28.59 hours after PO administration. The route of administration affected the time until maximum plasma concentration ([T.sub.max]), with plasma levels post-oral dosing levels reaching peak in 12.00 hours and post-intramuscular dosing reaching peak levels in 1 hour. Plasma concentrations were detectable through 96 hours via both routes of administration. Using the target plasma concentration of 3.4 [micro]g/mL found to be therapeutic in Hispaniolan Amazon parrots via a pharmacodynamic study, African penguin meloxicam plasma concentrations remained above or at this range for 24 and 48 hours after IM and PO administration, respectively. (17) Oral administration fell just below this concentration at 72 hours with 3.02 [micro]g/mL.

Overall, these results suggested that very similar exposure (AUC) would result from administering meloxicam by either route in penguins. The average relative bioavailability between these 2 formulations is close to 1. The major difference is related to the rate of absorption, which seems faster after intramuscular administration, as suggested by a significantly shorter [T.sub.max] (median IM, 1 hour vs median PO, 12 hours) and a significantly higher [C.sub.max] (54% higher on average). Differences in rate of absorption do not seem to cause a flip-flop effect, as the [t.sub.1/2] value was not significantly different between both routes of administration.

Our results highlight the varying drug metabolism of avian species. The pharmacokinetics of meloxicam in African penguins differs from published studies in other avian species. Plasma concentrations of meloxicam still were detectable at over 96 hours in African penguins but were of shorter detectable duration in other species. In Hispaniolan Amazon parrots, meloxicam plasma concentrations last 15.1 [+ or -] 7.7 hours after intramuscular administration and 15.8 [+ or -] 8.6 hours after oral administration. (16) American flamingos showed plasma durations under 8 hours for oral and intramuscular administration. (11) The duration of plasma meloxicam concentration in African penguins seems closer to that of some mammalian species, such as dogs (24 hours) and bottlenose dolphins (Tursiops truncata) (70 hours). (33,34)

The [t.sub.1/2] of meloxicam of 28.59 hours after oral administration and 31.87 hours after IM administration in African penguins also is longer than the [t.sub.1/2] reported in several other avian species. (16) Red-tailed hawks, great horned owls, and American flamingos had a very short [t.sub.1/2] after oral administration at 3.97 [+ or -] 0.32, 5.07 [+ or -] 4.5, and 3.83 [+ or -] 2.64 hours, respectively. (11, 13) American flamingos had a [t.sub.1/2] of 1.83 [+ or -] 1.22 hours after IM administration. (11) Comparatively, intravenous administration in red-tailed hawks and great horned owls also had a short [t.sub.1/2] at 0.49 [+ or -] 0.5 and 0.78 [+ or -] 52 hours, respectively. (13) African grey parrots seem to metabolize meloxicam more closely to African penguins and have a longer plasma [t.sub.1/2] after oral, intramuscular, and intravenous administration at 33.3 [+ or -] 1.22, 35.3 [+ or -] 6.1, and 31.4 [+ or -] 4.6 hours, respectively.12 No definitive explanation for the long plasma concentrations in some species exists, but the nature of meloxicam's CYP-dependent and cytochrome P450 enzyme metabolism and the species-specific amounts of each present a possible explanation for the vast differences appreciated in avian studies. (15,23)

Therapeutic concentrations of meloxicam are unknown for African penguins; therefore, therapeutic concentrations in psittacine species (3.45 [micro]g/ mL) were used as a target for penguins. (10,20,29) Therapeutic meloxicam plasma concentrations in Hispaniolan Amazon parrots often are used as target meloxicam plasma levels in the blood of birds. (17) This pharmacodynamic study in Hispaniolan Amazon parrots correlated plasma levels with clinical response to 3.45 [micro]g/mL, as the birds had improved weightbearing of an induced arthritic joint. Clinical response to meloxicam at 1 mg/kg lasted 12 hours in these parrots. (17) Human therapeutic plasma levels are much lower at 0.5 to 1.5 [micro]g/mL, further illustrating the differences between species. (35) A 1 mg/kg dose was selected in this study, especially considering the short duration of meloxicam levels detectable in plasma noted in other pharmacokinetic avian studies. Reported empirical avian doses for meloxicam range from 0.1 to 1 mg/kg. With information obtained in the pilot study in penguins, 1 mg/kg IM meloxicam was found to produce plasma levels exceeding the human and psittacine therapeutic range for the entire 96 hours. At doses of 0.5 and 0.25 mg/kg, the plasma levels were near or within the human and psittacine therapeutic range. (17,35) Plasma levels still were detectable through 96 hours after dosing. Oral dosing at 1 mg/kg produced plasma levels within the avian range through 48 hours (but detectable in plasma through 96 hours). The intramuscular route also had a higher [C.sub.max] than the oral route with a 1 mg/kg dosage, which was observed from the pilot study. A lower dose of 0.5 mg/kg was used in the main study for the intramuscular route to lower the peak plasma concentrations ([C.sub.max]) reached. A consideration for future studies is to extend collection points past 96 hours to further establish nondetectable limits. Repeat dosings of meloxicam are required to determine if meloxicam accumulates in the plasma. As demonstrated by the unique pharmacokinetics of meloxicam in penguins, each avian species may have different metabolism or response to medications such as meloxicam. Pharmacodynamic studies are needed to correlate the plasma concentration required to provide clinical analgesic relief.

Several studies have been performed to test the safety of meloxicam in avian species. Hispaniolan Amazon parrots, African gray parrots, and quail have been evaluated for numerous effects of meloxicam on the body. (21,23,24) Renal biopsy, fecal occult blood, biochemical values, complete blood count results, and behavior all have been evaluated with no evidence of negative effects after administration with meloxicam. (17, 22-25) Anecdotally, meloxicam has been used in over 700 species of birds. (4) No adverse effects have been noted thus far, in any species. (17,22-25) We have used meloxicam extensively in African penguins. However, as illustrated by the unique plasma concentrations of African penguins, studies with meloxicam focusing on renal, gastrointestinal, and hepatic side effects are still warranted.

Meloxicam is a COX-2 preferential NSAID, meaning that these prostaglandins related to inflammation and pain are reduced, while limiting the effect on COX-1, responsible for normal cell functions of tissues, such as macula densa, gastrointestinal tract, and central nervous system. This likely contributes to meloxicam having no noted adverse effects. Meloxicam is metabolized almost exclusively by the liver. It relies on P-450 and CYP-dependent mediated metabolism and is excreted in equal parts in the urine and feces, with significant biliary secretion, which can lead to prolonged absorption. (15,36) Administration of the medication with food could delay absorption, although this is not observed in humans or Hispaniolan Amazon parrots. Whether meloxicam undergoes hepatic recirculation is not known. Birds also have a more primitive kidney than mammals, with a mammalian-type nephron with shorter loops of Henle and a reptilian-like nephron that lacks a loop of Henle. This could aid in explanation of the lack of adverse effects seen in avian species with this medication. Hispaniolan Amazon parrots have been administered meloxicam at 1.6 mg/kg PO q12h for 15 days with no clinically relevant adverse effects (fecal occult blood, whole blood clotting time, or hematologic evaluation). (22) Penguins also have a unique anatomy. They are fish-eating birds that cannot fly; therefore, they have very developed pectoral muscles with high density myoglobin for quick and powerful movement through the water. They have a very short gastrointestinal tract with a small crop and low gastric pH for digesting prey with speed and efficiency. All of these penguin-specific traits could influence the metabolism of administered drugs. (6)

Nonsteroidal anti-inflammatory drugs such as meloxicam are commonly used drugs with a wide array of doses and frequencies that have been used in numerous species. African penguins are a commonly kept species and are part of SSP; therefore, providing information about drugs used to treat this species is important. Pharmacokinetic parameters should be established for each species due to pronounced metabolic and physiologic differences between species.

Jennilee Morrison, DVM, Cheryl B. Greenacre, DVM, Dipi ABVP (Avian, Exotic Companion Mammal), Robert George, DVM, Sherry Cox, PhD, and Tomas Martin-Jimenez, DVM, PhD, Dipi ACVCP, Dipi ECVPT

From the Departments of Small Animal Clinical Sciences (Morrison. Greenacre. George) and Biomedical Sciences and Diagnostic Sciences (Cox. Martin-Jimenez). College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996. USA.

Acknowledgments: We thank Ripley's Aquarium of the Smokies and Megan Klose for their time and effort involved in the project. Supported by the Companion Animal Fund Grant, University of Tennessee, College of Veterinary Medicine.

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Caption: Figure 1. Mean ([+ or -] standard deviation) plasma concentrations of meloxicam over 96 hours after a single administration of 1 mg/kg PO in 8 African penguins.

Caption: Figure 2. Mean ([+ or -] standard deviation) plasma concentrations of meloxicam over 96 hours after a single administration of 0.5 mg/kg IM in 8 African penguins.
Table 1. Pharmacokinetic parameters in 2 groups of 8 African
penguins after oral (1 mg/kg) and intramuscular (0.5 mg/kg)
administration of meloxicam.

                                         Oral
Pharmacokinetic parameter          median (min max)

[AUC.sub.0-Last],               432.32 (345.50-763.37)
hours * [micro]g/mL

[AUC.sub.0-[infinity]],         520.69 (354.08-856.69)
hours * [micro]g/mL

[AUC.sub.Extrap], %               11.63 (7.93-37.50)

[C.sub.max], [micro]g/mL          10.84 (7.06-21.98)

[MRT.sub.0-[infinity]], hours     48.37 (41.85-95.72)

Terminal [t.sub.1/2], hours       28.59 (25.43-60.61)

[T.sub.max], hours                12.00 (8.00-24.00)

                                     Intramuscular
Pharmacokinetic parameter          median (min max)

[AUC.sub.0-Last],               210.56 (146.72-408.95)
hours * [micro]g/mL

[AUC.sub.0-[infinity]],         238.79 (156.53-483.24)
hours * [micro]g/mL

[AUC.sub.Extrap], %               12.04 (6.27-17.80)

[C.sub.max], [micro]g/mL           8.03 (6.90-13.23)

[MRT.sub.0-[infinity]], hours     44.24 (31.79-54.93)

Terminal [t.sub.1/2], hours       31.87 (24.28-37.86)

[T.sub.max], hours                 1.00 (0.50-2.00)

Abbreviations: [AUC.sub.0-Last] indicates area under
the plasma concentration time curve from time 0 to last
time point; [AUC.sub.0-[infinity]], area under the plasma
concentration time curve from time 0 to infinity;
[AUC.sub.Extrap], percent of the [AUC.sub.0-[infinity]]
extrapolated to infinity: [C.sub.max]. maximum plasma
concentration: MRT. mean residence time; [t.sub.1/2],
terminal half-life: [T.sub.max] time to maximum
plasma concentration.
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Title Annotation:Original Study
Author:Morrison, Jennilee; Greenacre, Cheryl B.; George, Robert; Martin-Jimenez, Tomas
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Jun 1, 2018
Words:4845
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