Population pharmacokinetics of mavacoxib in osteoarthritic dogs

Cox, S. R., Liao, S., Payne‐Johnson, M., Zielinski, R. J., Stegemann, M. R. Population pharmacokinetics of mavacoxib in osteoarthritic dogs. J. vet. Pharmacol. Therap . 34 , 1–11. Mavacoxib (Trocoxil™) is an oral long‐acting COX‐2 inhibitor approved for the treatment of osteoarthritis in dogs. Two field trials were conducted in client‐owned dogs suffering from osteoarthritis, with dosages of 4 mg/kg body weight (BW) (Study 1) or 2 mg/kg BW (Study 2). Mavacoxib plasma concentrations were determined from trough blood samples and from blood samples collected at 4–10 months after the last dose. A one‐compartment linear model was fitted to the concentration data (1317 concentration records from 286 patients), and parameters for oral clearance ( Cl / F ), apparent volume of distribution (V d / F ) and their between‐subject variabilities (BSV) were estimated. Covariates were included in the model based on the outcomes of stepwise regression procedures. In the final model, the typical value of Cl / F was a function of BW, age and breed. German shepherds and Labrador retrievers were found to have 31% higher values of Cl / F than patients from different breeds with similar ages and BWs. The typical value of V d / F was found to be dependent only on BW. The two field studies appeared to differ similarly with respect to Cl / F and V d / F . The explanation for this difference is not known, but the difference was accounted for in the final model as a 23.9% lower bioavailability in Study 2. Mavacoxib exhibited relatively broad BSV in Cl / F and V d / F , with coefficients of variation of 47% and 19%, respectively. The typical value for mavacoxib’s terminal elimination plasma half‐life ( t 1/2 ) was 44 days, but a minority of patients (approximately 5%) had empirical Bayes estimates of t 1/2 exceeding 80 days. Simulations with the model indicated that the majority of patients treated with mavacoxib 2 mg/kg will maintain trough plasma mavacoxib concentrations associated with efficacy. Results of the population pharmacokinetic analysis helped to reduce the dose from 4 to 2 mg/kg and thus increased the therapeutic index for this molecule.