Application of new measures of nonlinearity to parameter estimation and simulations in individual pharmacokinetic analyses

Abstract

Since simulation studies are widely used in pharmacokinetics, it is necessary to ascertain their validity. An important, well-documented, concern that may negatively impact the validity of estimated parameters in pharmacokinetic models is existence of multiple minima of the criterion used in estimation. A presence of multiple minima causes instability of the estimates, dependence of the parameter estimates on the initial values, and bimodal (or, generally, multimodal) distributions of the estimated parameters. This paper offers a method to identify when these issues may occur by applying two new measures of nonlinearity.