Martin Fink (1), Ingrid Letellier (2), Mathieu Peyrou (3), Martin Jung(3), Jonathan N. King (4), Philippe Gruet (4), Jerome M. Giraudel (5)
(1) Novartis Pharma AG, Modeling & Simulation, CH-4002 Basel, Switzerland; (2) Novartis Santé Animale SAS, FR-92500 Rueil-Malmaison, France; (3) Novartis Centre de Recherche Santé Animale SA, CH-1566 Saint-Aubin, Switzerland; (4) Novartis Animal Health Inc, CH-4058 Basel, Switzerland; (5) Novartis Animal Health Australasia Pty Ltd, Research Centre, NSW 2178 Kemps Creek, Australia.
Objectives: A previous population analysis showed the preferential distribution of the coxib NSAID robenacoxib to inflamed joints in dogs [1]. The objective of this analysis was to further study the pharmacokinetic properties of robenacoxib in the target animal population (dogs suffering from chronic osteoarthritis) and to assess the influence of covariates such as age, weight, sex, and breed categories and the subsequent need of any dose adjustment.
Methods: Data was pooled from three different clinical studies including a total of 208 adult dogs with chronic osteoarthritis. Robenacoxib was administered orally as tablets and was quantified in blood using LC-MS analysis. A population pharmacokinetic model was developed using NONMEM and stepwise covariate search was performed with scm from the PsN. Figures were produced in R based on the empirical Bayes estimates from the final model.
Results: A two-compartment population model was identified to fit the pooled data well with sequential 0- and 1st-order absorption. Statistically significant effects on apparent clearance (and thus exposure) and central volume of distribution was found for weight only (p<0.01). Age, sex, and breed group were not found to significantly explain part of the remaining variability.
Conclusions: The presented population pharmacokinetic analysis provided insights in the necessary adjustment of dose for robenacoxib in the patient population, which would have been impossible using standard statistical approaches. The analysis supports the current recommended dose of 1-2 mg/kg body weight. The remaining unexplained variability in apparent clearance is minor compared to the approximately 2-fold range of exposure in the present dose range of 1-2 mg/kg body weight. No significant effects of age and breed on exposure support that no further dose adjustment is necessary.
References:
[1] Silber, HE et al., 2010. Population pharmacokinetic analysis of blood and joint synovial fluid concentrations of robenacoxib from healthy dogs and dogs with osteoarthritis. Pharm Res 27(12):2633-45.
Reference: PAGE 21 () Abstr 2362 [www.page-meeting.org/?abstract=2362]
Poster: Other Drug/Disease Modelling