Design optimization of longitudinal studies using metaheuristics: Application to lithium pharmacokinetics

Lithium is recommended as a first line treatment for patients with bipolar disorder. However, only certain patients show a good response to the drug, and the variability and tolerability of lithium response are poorly understood. Greater precision in the early identification of individuals who are likely to respond well to lithium is a significant unmet clinical need. We create optimal designs to better understand the pharmacokinetic exposition of lithium for patients with and without a genetic covariate. From a Fisher information matrix based method, we find different optimal designs for estimating various parameters in a complicated pharmacokinetics/pharmacodynamics nonlinear mixed effects model with multiple physician specified constraints. Our approach uses flexible state-of-the-art metaheuristics to find various types of efficient designs, including multiple-objective optimal designs that can balance the competitiveness of the objectives and deliver higher efficiencies for more important objectives. Results from this article will be used as part of a broader study to implement efficient designs to better understand the exposition of sustained-release lithium in patients with bipolar disorder.