Differential inhibition of cyclooxygenase isoenzymes in the cat by the NSAID robenacoxib

Abstract

Robenacoxib is a new nonsteroidal anti‐inflammatory drug (NSAID) developed for use in companion animal medicine. The objectives of this study were: to quantify the inhibitory actions of robenacoxib on cyclooxygenase (COX) isoenzymes in feline whole blood assays; to establish blood concentration–time profiles of robenacoxib after intravenous and subcutaneous dosing in the cat and; to predict the time courses of inhibition of COX isoforms by robenacoxib. COX‐1 and COX‐2 activities in heparinized feline whole blood samples were induced with calcium ionophore and lipopolysaccharide, respectively. Inhibition of thromboxane B₂ provided a marker of both COX‐1 and COX‐2 activities and a nonlinear parametric mixed effects modelling approach was used to establish the pharmacodynamic parameters describing this inhibition. Mean values (and prediction intervals) of IC₅₀ were 28.9 (16.4–51.1) μm (COX‐1) and 0.058 (0.010–0.340) μm (COX‐2). These parameters were used to compute several selectivity indices. Selectivity IC ratios (COX‐1:COX‐2) were 502.3 (IC₅₀/IC₅₀), 451.6 (IC₉₅/IC₉₅) and 17.05 (IC₂₀/IC₈₀). Based on a clinically recommended dosage regimen of 2 mg/kg, it was predicted that the corresponding mean robenacoxib blood concentration over the first 12 h after drug administration corresponded to 5% inhibition of COX‐1 and 90% inhibition of COX‐2.