Paw inflammation model in dogs for preclinical pharmacokinetic/pharmacodynamic investigations of nonsteroidal anti-inflammatory drugs

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 338; no. 2; pp. 548 - 558
• Main Authors: Jeunesse, E C, Bargues, I A, Toutain, C E, Lacroix, M Z, Letellier, I M, Giraudel, J M, Toutain, P L
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.08.2011
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical - methods; Female; Foot - pathology; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Lameness, Animal - drug therapy; Lameness, Animal - metabolism; Lameness, Animal - pathology; Life Sciences; Male; Pain Measurement - drug effects; Pain Measurement - methods; Random Allocation; Reproducibility of Results; Thiazines - pharmacokinetics; Thiazines - therapeutic use; Thiazoles - pharmacokinetics; Thiazoles - therapeutic use; clinical pharmacokinetics; rar; meloxicam; cox-2; dosage regimen; cat
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.110.178350

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 investigations for testing nonsteroidal anti-inflammatory drugs in dogs. A kaolin-induce 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 progressively resolved over 2 months. Five end points 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 measured regularly over the next 24 h 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 pharmacokinetic/pharmacodynamic model. This model described three effects of meloxicam, namely, classic anti-inflammatory, analgesic, and antipyretic effects. The mean plasma meloxicam IC(50) values 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 IC(50) values require approximately 80 (antipyretic effect) to 90% (all other effects) cyclooxygenase-2 inhibition as calculated ex vivo whole-blood assay data.