Optimal designs for composed models in pharmacokinetic-pharmacodynamic experiments.

We consider two frequently used PK/PD models and provide closed form descriptions of locally optimal designs for estimating individual parameters. In a novel way, we use these optimal designs and construct locally standardized maximin optimal designs for estimating any subset of the model parameters of interest. We do this by maximizing the minimal efficiency of the estimates across all relevant parameters so that these optimal designs are less dependent on the individual parameter or parameters of interest. Additionally, robust designs are proposed to further reduce the dependence on the nominal values of the parameters. We compare efficiencies of our proposed optimal designs with locally optimal designs and designs used in four real studies from the literature and show that our proposed designs provide advantages over those used in practice.