Abstract
Assessment of the time needed to attain steady state is a key pharmacokinetic objective during drug development. Traditional approaches for assessing steady state include ANOVA-based methods for comparing mean plasma concentration values from each sampling day, with either a difference or equivalence test. However, hypothesis-testing approaches are ill suited for assessment of steady state. This paper presents a nonlinear mixed effects modelling approach for estimation of steady state attainment, based on fitting a simple nonlinear mixed model to observed trough plasma concentrations. The simple nonlinear mixed model is developed and proposed for use under certain pharmacokinetic assumptions. The nonlinear mixed modelling estimation approach is described and illustrated by application to trough data from a multiple dose trial in healthy subjects. The performance of the nonlinear mixed modelling approach is compared to ANOVA-based approaches by means of simulation techniques. Copyright © 2005 John Wiley & Sons, Ltd.
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