Abstract
Meloxicam is a widely used nonsteroidal anti-inflammatory drug in avian species. However, variability in pharmacokinetic (PK) and pharmacodynamic (PD) parameters in birds warrants species-specific studies for dose and dosing interval optimization. We performed a perioperative PK study of meloxicam (0.5mg/kg, intravenously) on emus of three different age groups: 3 chicks (5weeks old, 3.5kg), 4 juveniles (26weeks old, 18.8kg) and 6 adults (66weeks old, 38.8kg). A two-compartment population PK model including weight as a significant covariate on clearance and central volume of distribution (V1) best fitted the data. The typical values (20kg bird) for clearance and V1 were 0.54L/kg/h and 0.095L/kg. Both parameters significantly decreased with increasing weight/age. Meloxicam potency and selectivity for COX-1 and COX-2 were measured in whole blood assays (TxB2 production endpoint). Meloxicam was partially selective in emus (IC50 COX-1:COX-2=9.1:1). At the current empirical dose (0.5mg/kg/24hr), plasma meloxicam concentration is above IC50 of COX-2 for only 2hr. PK/PD predicted dose required for 80% COX-2 inhibition over 24hr were 3.4, 1.4 and 0.95L/kg/day in chicks, juveniles and adult emus, respectively. The safety, therapeutic efficacy and practicality of modifying the daily dose or dose interval should be considered for dose recommendations in emus.
Highlights
Nonsteroidal anti-inflammatorie drugs (NSAIDs) are an important component of pain management in veterinary species, with meloxicam being widely available in clinical practice
This study hypothesizes that there are significant differences in the PK of meloxicam between emus of three different age groups and the empirical dosage regime may be too low in this species. This will be achieved through the following objectives: (a) investigate the effect of age on the main parameters after a single IV bolus by performing PK analysis of meloxicam for the three age groups under general anaesthesia, (b) compute the potency of meloxicam against COX-1 and COX-2 from whole blood assays through PD analysis and (c) calculate the duration of COX-2 and COX-1 inhibition and define an ideal dosage regime and anaesthetic protocol in this species
The models used produced a negative value of I0 compared with the control for both COX-1 and COX-2, indicating that at very low concentrations of meloxicam some TxB2 stimulation had TA B L E 3 Summary of pharmacodynamic parameters of COX-1 and COX-2 inhibition by meloxicam by whole blood assay
Summary
Nonsteroidal anti-inflammatorie drugs (NSAIDs) are an important component of pain management in veterinary species, with meloxicam being widely available in clinical practice. Variability of PK parameters between individuals can result in differing plasma concentration–time courses despite administration of the same dose per unit body weight This is due to intrinsic variation within a population of factors including genetics, disease status, age and concurrent drug therapy (Buclin et al, 2009). Similar changes in PK parameters have been reported, which can be linked to maturational changes in kidney and liver function, as well as in body water/fat composition (Gasthuys et al, 2017; Millecam et al, 2019) In this respect, growing conventional piglets have been recently studied as surrogate large animal model in paediatric drug research (Millecam, et al, 2019). This will be achieved through the following objectives: (a) investigate the effect of age on the main parameters after a single IV bolus by performing PK analysis of meloxicam for the three age groups under general anaesthesia, (b) compute the potency of meloxicam against COX-1 and COX-2 from whole blood assays through PD analysis and (c) calculate the duration of COX-2 and COX-1 inhibition and define an ideal dosage regime and anaesthetic protocol in this species
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