The goal of the present study was to develop and validate a new canine model of inflammation. The motivation was to make available a scientifically appropriate and ethically acceptable model to conduct Pharmacokinetic/Pharmacodynamic (PK/PD) investigations for testing non-steroidal anti-inflammatory drugs (NSAIDs) in dogs. A kaolin-paw inflammation model previously developed in cats was adapted to the dog. The paw inflammation developed within a few hours, reached maximum values 24 h and up to 3 days after kaolin administration and then the inflammation progressively resolved over 2 months. Five endpoints of clinical interest (body temperature, creeping time under a tunnel, paw withdrawal latency to a standardized thermal stimulus, lameness score and vertical force developed during walking on a force plate) were regularly measured over the next 24 hours and beyond, to characterize the time development of the inflammation either in control conditions (placebo period) or after the administration of meloxicam (test period) according to a crossover design. Pharmacodynamic data were modeled using an indirect response PK/PD model. This model described three effects of meloxicam, namely classical anti-inflammatory, analgesic and antipyretic effects. The mean plasma meloxicam IC50 were 210 ng/mL for the antipyretic effect, 390 ng/mL for the analgesic effect, and 546 ng/mL for the vertical force exerted by the paw on the ground as measured by force plates. These in vivo IC50 require about 80 (antipyretic effect) to 90% (all others effects) of the COX-2 inhibition as calculated ex vivo whole blood assay data.
- Received December 17, 2010.
- Revision received April 26, 2011.
- Accepted April 26, 2011.
- The American Society for Pharmacology and Experimental Therapeutics