Pharmacokinetics of a Sustained-release Formulation of Meloxicam After Subcutaneous Administration to Hispaniolan Amazon Parrots (Amazona ventralis)

Abstract

Meloxicam has been shown to have a safe and favorable pharmacodynamic profile with individual variability in Hispaniolan Amazon parrots (Amazona ventralis). In the current study, we determined the pharmacokinetics of a sustained-release formulation of meloxicam after subcutaneous administration to Hispaniolan Amazon parrots. Twelve healthy adult parrots, 6 males and 6 females, were used in the study. Blood samples were collected before (time 0) and at 0.5, 1, 2, 6, 12, 24, 48, 72, 96, and 120 hours after a single dose of the sustained-release meloxicam formulation (3 mg/kg SC). Plasma meloxicam concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. Plasma concentrations reached a mean C of 23.4 μg/mL (range, 14.7-46.0 μg/mL) at 1.8 hours (range, 0.5-6 hours), with a terminal half-life of 7.4 hours (range, 1.4-40.9 hours). Individual variation was noticeable, such that some parrots (4 of 12 birds) had very low plasma meloxicam concentrations, similar to the high variability reported in a previous pharmacokinetic study of the standard meloxicam formulation in the same group of birds. Two birds developed small self-resolving scabs at the injection site. On the basis of these results, the sustained-release meloxicam formulation could be administered every 12 to 96 hours in Hispaniolan Amazon parrots to manage pain. Because of these highly variable results, the use of this formulation in this species cannot be recommended until further pharmacokinetic, safety, and pharmacogenomic evaluations are performed to establish accurate dosing recommendations and to understand the high pharmacokinetic variability.

Preliminary Evaluation of Sustained-release Compared with Conventional Formulations of Meloxicam in Sheep (Ovis aries)

“…Similar separations of clearance rates of SRM have been described in other species. 13,21 The variability of drug plasma concentrations we observed in our sheep could be due to a variety of reasons related to absorption and clearance. Meloxicam, similar to most NSAID, is highly protein bound (greater than 99%) and can be distributed into the extracellular space as well as penetrate other tissues 38 and may give rise to altered pharmacokinetics in situations where albumin concentration might vary (for example, surgical insult, disease states, perfusion changes, and inflammation).…”

“…Similar patterns of clearance rate have been described for SRM in other species. 13,21 The ratio of SRM:CM plasma levels during the first 24 h was between 2.88 (95% CI, 1.95 to 4.25) at 4 h and 4.23 (95% CI, 2.86 to 6.25) at 24 h ( Figure 2). There were no significant differences at 36, 48, and 120 h (P = 0.16, P = 0.42, and P = 0.42, respectively).…”

“…Alternatively, inconsistencies of the polymer matrix formulation pertaining to its release and absorption rates at the injection site might be present. Other reasons for pharmacokinetic differences might reflect characteristics of the individual animals, such as size, age, metabolism, and body composition, 13 although we tried to acquire animals within similar ranges. As ruminants, sheep possess a complex gastric system that can affect drug distribution bioavailability.…”

“…With several SR drug classes on the market (for example, opioids, local analgesics and anesthetics, NSAID), multimodal analgesia using these formulations are being further explored, because they may effectually improve animal welfare in a variety of species. 3,6,13,19,21,32,39 Previous studies in biomedical sheep have demonstrated that SR buprenorphine reaches steady plasma concentrations and provides continuous analgesia against thermal nociception for at least 72 h. 39 In addition, liposomal bupivacaine has been evaluated as a SR local analgesic product for the prevention of transduction and transmission of acute and perioperative pain lasting 4 d in a rat model 19 and as long as 72 h in dogs. 22 The NSAID meloxicam belongs to the enolic acid class and has antiinflammatory, analgesic, and antipyretic properties.…”

“…40 Studies evaluating SR meloxicam (SRM) in several species have yielded variable results. At the recommended rodent dose (4 mg/kg SC once), mechanical hypersensitivity-but not thermal hypersensitivity-was attenuated for a maximum of 48 h in a rat incisional pain model, 32 and in mice, plasma levels of SRM were sustained for at least 24 h, but therapeutic levels were maintained for only 12 h. 21 In amazon parrots, SRM showed highly variable results, with maintenance of target plasma concentrations for 12 to 96 h, 13 yet in cynomolgus macaques, SRM achieved adequate steadystate plasma concentrations for 48 to 72 h, demonstrating more consistent levels than other formulations that required daily dosing. 3 An ideal SR NSAID would maintain therapeutic efficacy for at least 72 h, with at most minimal disruption to renal and hepatic function.…”