In vitro and ex vivo inhibition of COX isoforms by robenacoxib in the cat: a comparative study.

Robenacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID) developed for use in companion animals. Whole blood assays were used to characterize in the cat the pharmacodynamics of robenacoxib for inhibition of the cyclooxygenase (COX) isoforms, COX-1 and COX-2, in comparison with other NSAIDs. Based on in vitro IC(50) COX-1:IC(50) COX-2 ratios, robenacoxib was COX-2 selective (ratio = 32.2), diclofenac (ratio = 3.9) and meloxicam (ratio = 2.7) were only weakly COX-2 preferential, and ketoprofen (ratio = 0.049) was COX-1 selective. In an in vivo pharmacokinetic ex vivo pharmacodynamic study, after both p.o. (1-2 mg/kg) and subcutaneous (2 mg/kg) dosing, robenacoxib achieved peak blood concentrations rapidly (T(max) = 1 h for both administration routes) and was cleared from blood relatively rapidly (mean residence time was 1.70 h after p.o. and 1.79 h after subcutaneous dosing). In ex vivo COX isoform inhibition assays, orally (1-2 mg/kg) or subcutaneously (2 mg/kg) administered robenacoxib significantly inhibited COX-2, with a relatively short duration of action in the central compartment, and had no effect on COX-1. Therefore robenacoxib was COX-2 selective and spared COX-1 in vivo. In contrast, meloxicam (0.3 mg/kg via subcutaneous injection) inhibited both COX-1 and COX-2 isoforms significantly for at least 24 h, indicating nonselectivity in vivo.

Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in dog.

The objectives of this study were to establish dose-response and blood concentration-response relationships for robenacoxib, a novel nonsteroidal anti-inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)-2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra-articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX-1 and COX-2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose-related improvement in weight-bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED(50) was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti-inflammatory effects of robenacoxib were significantly superior to placebo (0.25-4 mg/kg robenacoxib) and were non-inferior to meloxicam (0.5-4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose-related inhibition of COX-2 (estimated ED(50) was 0.52 mg/kg) but no inhibition of COX-1. At a dosage of 1-2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.