Population Pharmacokinetic Analysis of Blood and Joint Synovial Fluid Concentrations of Robenacoxib from Healthy Dogs and Dogs with Osteoarthritis
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The purpose of this population analysis was to characterize the pharmacokinetic properties of robenacoxib in blood and stifle joint synovial fluid of dogs.
Data were obtained from two studies: 1) 8 healthy Beagle dogs in which an acute inflammation was induced by injection of urate crystals into one joint; 2) 95 dogs from various breeds diagnosed with osteoarthritis (OA). Robenacoxib concentrations in blood and synovial fluid were measured using a validated HPLC-UV and LC-MS method. Non-linear mixed effects modeling was performed using NONMEM6.
A two-compartment pharmacokinetic model with linear elimination was developed to describe blood concentrations of robenacoxib. Blood clearance in healthy animals was found to be 75% higher than in OA dogs. Synovial fluid concentrations were modeled using an effect-compartment-type model predicting longer residence times in OA dogs compared to healthy Beagles (e.g. concentrations above the IC50 for COX-2, respectively, 16 h vs. 10 h at 1.5 mg/kg).
Robenacoxib was found to reside longer at the effect site (inflamed joint) compared to blood in both healthy and OA dogs. These results may explain the good efficacy observed with once-daily dosing in clinical trials and the high safety index of robenacoxib in dogs.
KEY WORDSCOXIB dog robenacoxib tissue selectivity
below limit of quantification
first-order conditional estimation method
high pressure liquid chromatography with ultraviolet detection
liquid chromatography with mass spectrometry
lower limit of quantification
Mean Transit Time
number of transit compartments
non-steroidal anti-inflammatory drug
objective function value
international cooperation on harmonisation of technical requirements for registration of veterinary medicinal products
visual predictive check
This work was sponsored by Novartis Animal Health Inc., CH-4058 Basel, Switzerland.
- 7.Gruet P, Seewald W, King JN. Subcutaneous and oral robenacoxib versus meloxicam for the treatment of acute pain and inflammation associated with orthopedic surgery in dogs; a randomized, non-inferiority field study. Am J Vet Res. 2010; accepted for publication.Google Scholar
- 8.Reymond N, Speranza C, Gruet P, Seewald W, King JN. Robenacoxib versus carprofen for the treatment of canine osteoarthritis; a randomized, non-inferiority field study. J Vet Pharmacol Therap. 2010; submitted for publication.Google Scholar
- 9.King JN, Arnaud JP, Goldenthal EI, Gruet P, Jung M, Seewald W, Lees P. Robenacoxib in the dog: target species safety in relation to extent and duration of inhibition of COX-1 and COX-2. J Vet Pharmacol Therap. 2010; doi: 10.1111/j.1365-2885.2010.01209.x.
- 18.Beal SL. Ways to fit a PK model with some data below the quantification limit. J Pharmacokinet Biopharm. 2001;28(5):481–504.Google Scholar