Further developments of the Fisher information matrix in nonlinear mixed effects models with evaluation in population pharmacokinetics.

We extend the development of the expression of the Fisher information matrix in nonlinear mixed effects models for designs evaluation. We consider the dependence of the marginal variance of the observations with the mean parameters and assume an heteroscedastic variance error model. Complex models with interoccasions variability and parameters quantifying the influence of covariates are introduced. Two methods using a Taylor expansion of the model around the expectation of the random effects or a simulated value, using then Monte Carlo integration, are proposed and compared. Relevance of the resulting standard errors is investigated in a simulation study with NONMEM.