Modeling of Large Pharmacokinetic Data Using Nonlinear Mixed‐Effects: A Paradigm Shift in Veterinary Pharmacology. A Case Study With Robenacoxib in Cats

Abstract

The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed‐effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects. A bicompartmental disposition model with simultaneous zero and first‐order absorption best described robenacoxib PKs in blood. Clearance was 0.502 L/kg/h and the bioavailability was high (78%). The absorption constant point estimate (Ka = 0.68 h−1) was lower than beta (median, 1.08 h−1), unveiling flip‐flop kinetics. No dosing adjustment based on available covariates information is advocated. This modeling work constitutes the first application of NLME in a large feline population.

Mathematical modeling and simulation in animal health. Part III: Using nonlinear mixed‐effects to characterize and quantify variability in drug pharmacokinetics

“…Over the past 15 years, several peer‐reviewed NLME analyses in veterinary pharmacology have been published. The most recent examples include the study of topiramate in epileptic dogs (Vuu et al., ); nonsteroidal anti‐inflammatory drug (NSAIDs) in dogs and cats with osteoarthritis (Cox, Liao, Payne‐Johnson, Zielinski, & Stegemann, ; Fink et al., ; Pelligand, Soubret, King, Elliott, & Mochel, ; Silber et al., ); tobramycin in horses (Haritova, Bakalov, Hubenov, & Lashev, ); valnemulin and cefquinome in pigs (Zhao et al., , ); tulathromycin in lactating goats (Lin, Cuneo et al., ; Lin, Gehring et al., ); and penicillin G in cattle and swine (Li et al., ).…”

“…Finally, Pelligand et al. () used NLME to characterize feline robenacoxib disposition kinetics in 83 cats, pooling data from across seven preclinical (laboratory) studies and one field (client‐owned cats, perioperative sampling) study, in order to evaluate the effect of anesthesia on robenacoxib PK. Using individual parameter estimates, robenacoxib concentration vs time profiles were generated to determine the time interval during which plasma levels remained above a target PD threshold, for example, IC 80 COX 2 and IC 20 COX 1 for efficacy and safety assessment, respectively.…”

“…Another therapeutic indication where NLME has been used for dose selection and covariate identification of NSAIDs in companion animals is osteoarthritis (OA) (Cox et al, 2011;Fink et al, 2013;Pelligand et al, 2016;Silber et al, 2010).…”

Optimal Scheduling of Bevacizumab and Pemetrexed/Cisplatin Dosing in Non‐Small Cell Lung Cancer

“…ϕ 2 . The full posterior distribution of the parameters were used in place of empirical Bayes estimates to avoid visual artifacts as a result of shrinkage as suggested by Lavielle and Ribba and Pelligand et al . Statistical correlations between random effects were also numerically assessed using a Pearson correlation test at a P < 0.05 threshold.…”

Population variability in animal health: Influence on dose‐exposure‐response relationships: Part II: Modelling and simulation

“…Within animal health, published examples of NLME modelling are also available (e.g. Silber et al., ; Cox, Liao, Payne‐Johnson, Zielinski, & Stegemann, ; Fink et al., ; Pelligand, Soubret, King, Elliott, & Mochel, ; Mochel & Danhof, ; Mochel et al., ; Mochel, Fink, et al., ; Mochel, Fink, et al., ) and have been described in a recent review article by Bon et al. ().…”