Automated covariate model building within NONMEM

Abstract

Purpose: One important task in population pharmacokinetic/pharmacodynamic model building is to identify the relationships between the parameters and demographic factors (covariates). The purpose of this study is to present an automated procedure that accomplishes this. The benefits of the proposed procedure over other commonly used methods are (i) the covariate model is built for all parameters simultaneously, (ii) the covariate model is built within the population modeling program (NONMEM) giving familiar meaning to the significance levels used, (iii) it can appropriately handle covariates that varies over time and (iv) it is not dependent on the quality of the posterior Bayes estimates of the individual parameter values. For situations in which the computer run-times are a limiting factor, a linearization of the non-linear mixed effects model is proposed and evaluated.

Methods: The covariate model is built in a stepwise fashion in which both linear and non-linear relationships between the parameters and covariates are considered. The linearization is basically a linear mixed effects model in which the population predictions and their derivatives with respect to the parameters are fixed from a model without covariates. The stepwise procedure as well as the linearization was evaluated using simulations in which the covariates were taken from a real data set.

Results: The covariate models identified agreed well with what could be expected based on the covariates that were actually supported in each of the simulated data sets. The predictive performance of the linearized model was close to that of the non-linearized model.

Conclusions: The proposed procedure identifies covariate models that are close to the model supported by the data set as well as being useful in the prediction of new data. The linearized model performs nearly as well as the non-linearized model.