Non-Linear Mixed-Effects Pharmacokinetic Modeling of the Novel COX-2 Selective Inhibitor Vitacoxib in Cats

Abstract

The objective of this study was to develop a non-linear mixed-effects (NLME) model to describe the disposition kinetics of vitacoxib in cats following intravenous (I.V) and oral (P.O) (single and multiple) dosing. Data from six consecutive studies with 16 healthy neutered domestic short hair cats were pooled together to build a pharmacokinetic (PK) model using NLME. Population PK parameters were estimated using the stochastic approximation expectation maximization (SAEM) algorithm implemented in Monolix 2019R2. A two-compartment mammillary disposition model with simultaneous zero- and first-order absorption best described the PK of vitacoxib in plasma after oral dosing. The systemic CL of vitacoxib was found to be low (110 ml/h), with a steady-state volume of distribution (VSS) of 3.42 L in cats. Results from the automated covariate search in Monolix 2019R2 showed that bodyweight had a significant effect on the central volume of distribution of vitacoxib. Lastly, using Monte Carlo simulations, we investigated the time course of several dosages of vitacoxib from 0.01 to 8 mg/kg. Using this simulation set, we found a range of reasonable dosages that produce therapeutic plasma concentrations of vitacoxib for 24 h or more in cats.