Nonlinear mixed-effects models for pharmacokinetic data analysis: assessment of the random-effects distribution.

Nonlinear mixed-effects models are frequently used for pharmacokinetic data analysis, and they account for inter-subject variability in pharmacokinetic parameters by incorporating subject-specific random effects into the model. The random effects are often assumed to follow a (multivariate) normal distribution. However, many articles have shown that misspecifying the random-effects distribution can introduce bias in the estimates of parameters and affect inferences about the random effects themselves, such as estimation of the inter-subject variability. Because random effects are unobservable latent variables, it is difficult to assess their distribution. In a recent paper we developed a diagnostic tool based on the so-called gradient function to assess the random-effects distribution in mixed models. There we evaluated the gradient function for generalized liner mixed models and in the presence of a single random effect. However, assessing the random-effects distribution in nonlinear mixed-effects models is more challenging, especially when multiple random effects are present, and therefore the results from linear and generalized linear mixed models may not be valid for such nonlinear models. In this paper, we further investigate the gradient function and evaluate its performance for such nonlinear mixed-effects models which are common in pharmacokinetics and pharmacodynamics. We use simulations as well as real data from an intensive pharmacokinetic study to illustrate the proposed diagnostic tool.