Preclinical pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase‐2

Abstract

pharmacology of robenacoxib: a novel selective inhibitor of cyclooxygenase-2. J. vet. Pharmacol. Therap. 32,[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] This manuscript reports the results of preclinical studies in the rat with robenacoxib, a novel selective cyclooxygenase (COX)-2 inhibitor. Robenacoxib selectively inhibited COX-2 in vitro as evidenced from COX-1:COX-2 IC 50 ratios of 27:1 in purified enzyme preparations and >967:1 in isolated cell assays. Binding to COX-1 was rapid and readily reversible (dissociation t 1 ⁄ 2 << 1 min), whilst COX-2 binding was slowly reversible (t 1 ⁄ 2 = 25 min). In vivo, robenacoxib inhibited PGE 2 production (an index of COX-2 inhibition) in lipopolysaccharide (LPS)-stimulated air pouches (ID 50 0.3 mg ⁄ kg) and for at least 24 h in zymosan-induced inflammatory exudate (at 2 mg ⁄ kg). Robenacoxib was COX-1 sparing, as it inhibited serum TxB 2 synthesis ex vivo (an index of COX-1 inhibition) only at very high doses (100 mg ⁄ kg but not at 2-30 mg ⁄ kg). Robenacoxib inhibited carrageenan-induced paw oedema (ID 50 0.40-0.48 mg ⁄ kg), LPS-induced fever (ID 50 1.1 mg ⁄ kg) and Randall-Selitto pain (10 mg ⁄ kg). Robenacoxib was highly bound to plasma protein (99.9% at 50 ng ⁄ mL in vitro). After intravenous dosing, clearance was 2.4 mL ⁄ min ⁄ kg and volume of distribution at steady-state was 306 mL ⁄ kg. Robenacoxib was preferentially distributed into inflammatory exudate; the AUC for exudate was 2.9 times higher than for blood and the MRT in exudate (15.9 h) was three times longer than in blood (5.3 h). Robenacoxib produced significantly less gastric ulceration and intestinal permeability as compared with the reference nonsteroidal anti-inflammatory drug (NSAID), diclofenac, and did not inhibit PGE 2 or 6-keto PGF 1a concentrations in the stomach and ileum at 30 mg ⁄ kg. Robenacoxib also had no relevant effects on kidney function at 30 mg ⁄ kg. In summary, results of preclinical studies in rats studies suggest that robenacoxib has an attractive pharmacological profile for potential use in the intended target species, cats and dogs.(Paper

Population Pharmacokinetic Analysis of Blood and Joint Synovial Fluid Concentrations of Robenacoxib from Healthy Dogs and Dogs with Osteoarthritis

“…Since lumiracoxib and other acidic NSAIDs have demonstrated higher concentrations and longer residence times in inflammatory exudate compared to blood (11,12), it was hypothesized that robenacoxib would display similar tissue selectivity as other weakly acidic NSAIDs. In a tissue cage model in rats, average concentrations were 2.9 times higher, and the mean residence time was 3 times longer (15.9 h versus 5.3 h) for robenacoxib in inflammatory exudate compared to blood (4). However, tissue cages are only models for joints, and robenacoxib is used clinically in cats and dogs.…”

“…COXIBs remain, nevertheless, an interesting class of NSAIDs, with a favorable risk-benefit ratio, especially in cats and dogs which are especially sensitive to non-selective NSAIDs and in which an increased risk of cardiovascular side effects with NSAIDs has not been reported so far. Robenacoxib is a novel and highly selective inhibitor of COX-2 in cats and dogs (3)(4)(5) and is now available in several European countries for the treatment of pain and inflammation in cats and dogs (Onsior® injection and tablets). Robenacoxib shows more than one-hundred-fold selectivity for COX-2 compared to COX-1 in dogs in vitro using the whole blood assay (5).…”

Comparison of Oral Robenacoxib and Carprofen for the Treatment of Osteoarthritis in Dogs: A Randomized Clinical Trial

“…Robenacoxib is a new coxib NSAID, developed solely for companion animal use [8]. It is highly selective for the cyclo-oxygenase (COX)-2 enzyme in dogs.…”

The mouse and the rat in surgical research. The anesthetic approach

“…The data demonstrate that robenacoxib has potent analgesic, anti-inflammatory and antipyretic properties. Moreover, consistent with its weak activity as an inhibitor of COX-1, in the rat the gastric and intestinal tolerability of robenacoxib was significantly better than that of diclofenac, which non-selectively inhibits both COX-1 and COX-2 (King et al, 2009).…”