Pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus)

Abstract

OBJECTIVE To examine the pharmacokinetics and ex vivo pharmacodynamics of oral firocoxib administration in New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS 6 healthy New Zealand White rabbits. PROCEDURES Pharmacokinetics were determined from plasma concentrations measured via ultra performance liquid chromatography-tandem mass spectrometry after oral administration of firocoxib at a dose of 3.74 to 4.20 mg/kg. Pharmacokinetic analysis was performed using non compartmental methods. Pharmacodynamics of firocoxib were evaluated by measuring plasma concentrations of thromboxane and prostaglandin via ELISAs as surrogate markers of cyclooxygenase enzyme isoform inhibition. RESULTS The terminal rate constant was 0.07 hours (range, 0.05 to 0.11 h). The mean maximum concentration (Cmax) and time to Cmax were 0.16 µg/mL and 3.81 hours (range, 2.0 to 8.0 h), respectively. Mean residence time was 15.02 hours. Mean elimination half-life was 9.12 hours. For the pharmacodynamic analysis, firocoxib administration did not demonstrate a significant difference between any time point for prostaglandin E2 and only a significant difference between 24 and 48 hours for thromboxane B2. CLINICAL RELEVANCE Although the pharmacokinetic research supports that plasma firocoxib concentrations that would be therapeutic in dogs are achieved in rabbits, the pharmacodynamic results do not demonstrate a significant difference in levels of cyclooxygenase-2 inhibition, which indirectly reflects the anti-inflammatory effects of the drug. Further pharmacodynamic studies and multidose studies are warranted to determine the efficacy and safety of this drug in rabbits.

Examination of the pharmacokinetics and differential inhibition of cyclooxygenase isoenzymes in New Zealand white rabbits (Oryctolagus cuniculus) by the Non‐Steroidal anti‐inflammatory Robenacoxib

“…The individual variation in C max between the rabbits in the study was also wide (0.12-0.47 μg/ml for oral administration and 4.24-9.10 μg/ml for subcutaneous administration). This warrants consideration when choosing between this medication and other non-steroidal anti-inflammatory medications with less variability in C max to potentially achieve more consistent results in clinical use (Gardhouse et al, 2022).…”

“…Robenacoxib analysis was conducted by adapting methods for firocoxib in rabbits (Gardhouse et al, 2022). Briefly, frozen samples and standards (robenacoxib and robenacoxib‐d3 (Sigma‐Aldrich)) were thawed at room temperature and rigorously vortexed once completely thawed.…”

“…Plasma PGE 2 concentrations were determined using methods previously described (Gardhouse et al, 2022; Fraccaro et al, 2013; Kleinhenz et al, 2018). In brief, prior to sample processing, lipopolysaccharide (LPS) solution from Escherichia coli O111:B4 was created to a concentration of 1 mg/ml by adding 10 ml of phosphate buffered saline with a serological pipette using 10 mg of LPS.…”

Pharmacokinetics of mavacoxib in New Zealand White rabbits (Oryctolagus cuniculus)

“…The only pharmacokinetic studies of NSAIDs in rabbits currently are for meloxicam and firicoxib, and both were found to have a short half-life and therefore require a frequent dosing interval. [4][5][6] Previous pharmacokinetic studies of mavacoxib in mammalian species have been limited to the domestic dog, 2,3 where one study showed that a single 2 mg/kg PO dose reached therapeutic plasma concentrations for the management of osteoarthritis. 3 Mavacoxib has also been studied in a limited number of avian species, including the cockatiel (Nymphicus hollandicus), 7,8 the flamingo (Phoenicopterus ruber ruber), 9 and the African grey parrot (Psittacus erithacus).…”