Pharmacokinetic Modeling

Nonlinear Mixed-Effects Pharmacokinetic Modeling of the Novel COX-2 Selective Inhibitor Vitacoxib in Dogs

In this manuscript, we use a nonlinear mixed effects (NLME) framework to develop a compartmental model of vitacoxib disposition kinetics in dogs after intravenous (I.V), oral (P.O) and subcutaneous (S.C) dosing. The influence of age, sex, bodyweight and food intake were evaluated as covariates on model parameters to assess the need for dose adjustment of vitacoxib in dogs.

Our joint clinical and preclinical research team has been involved in the investigation of vitacoxib pharmacology, including pharmacokinetics and pharmacodynamics, for over a decade. Data produced for this work were pooled from four consecutive pharmacokinetic studies in which vitacoxib was given in various dosing regimens and administration routes to healthy beagle dogs. Individual plasma concentration vs. time data were simultaneously used in fitting a structural disposition model using the stochastic approximation expectation maximization (SAEM) algorithm for NLME as implemented in Monolix version 2018R2. In brief, a two-compartmental disposition model with first-order elimination and first-order absorption after P.O and S.C dosing best described the pharmacokinetics of vitacoxib in dogs. Our results showed that vitacoxib has a low systemic clearance and a low global extraction ratio but is largely distributed, probably due to its lipophilic nature. The absolute bioavailability of vitacoxib was estimated to be low to moderate, while results from the covariate analysis confirmed the need for BW adjustment with vitacoxib in dogs and suggest that vitacoxib be given with food to increase its oral bioavailability.

This work was presented at Journal of Veterinary Pharmacology and Therapeutics.

Vitacoxib in Dogs