title: Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation.
abstract: Robenacoxib is a novel nonsteroidal anti-inflammatory drug developed for use in cats. It is a highly selective COX-2 inhibitor. Results from previous feline studies showed that, despite a short half-life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib's pharmacokinetics and its ex vivo and in vivo selectivity for COX-1 and COX-2 using serum TxB(2) and exudate PGE(2) as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54-0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX-1 in blood was transient, occurring only at high concentrations, but inhibition of COX-2 in exudate persisted to 24 h. The potency ratio (IC(50) COX-1: IC(50) COX-2) was 171:1, and slopes of the concentration-effect relationship were 1.36 and 1.12 for COX-1 and COX-2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once-daily administration.
authors.affiliation: Royal Veterinary College, Department of Veterinary Basic Sciences, Hatfield, Herts, UK. lpelligand@rvc.ac.uk
authors.forename: L
authors.initials: L
authors.lastname: Pelligand
authors.forename: J N
authors.initials: JN
authors.lastname: King
authors.forename: P L
authors.initials: PL
authors.lastname: Toutain
authors.forename: J
authors.initials: J
authors.lastname: Elliott
authors.forename: P
authors.initials: P
authors.lastname: Lees
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D002371:Cat Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D002415:Cats; D018592:Cross-Over Studies; D015194:Diffusion Chambers, Culture; D015232:Dinoprostone / Q000097:blood / Q000378:metabolism; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D010648:Phenylacetates / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011453:Prostaglandins / Q000097:blood; D013929:Thromboxane B2 / Q000097:blood / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010648:Phenylacetates; D011453:Prostaglandins; D013929:Thromboxane B2; D004159:Diphenylamine; D015232:Dinoprostone; C551524:robenacoxib