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Interpretation of simulation studies for efficient estimation of population pharmacokinetic parameters
E I Ette1, A W Kelman, C A Howie
1Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Gardiner Institute, Scotland.
Objective:
To develop new approaches for evaluating results obtained from simulation studies used to determine sampling strategies for efficient estimation of population pharmacokinetic parameters.
Methods:
One-compartment kinetics with intravenous bolus injection was assumed and the simulated data (one observation made on each experimental unit [human subject or animal]), were analyzed using NONMEM. Several approaches were used to judge the efficiency of parameter estimation. These included: (1) individual and joint confidence intervals (CIs) coverage for parameter estimates that were computed in a manner that would reveal the influence of bias and standard error (SE) on interval estimates; (2) percent prediction error (%PE) approach; (3) the incidence of high pair-wise correlations; and (4) a design number approach. The design number (phi) is a new statistic that provides a composite measure of accuracy and precision (using SE).
Results:
The %PE approach is useful only in examining the efficiency of estimation of a parameter considered independently. The joint CI coverage approach permitted assessment of the accuracy and reliability of all model parameter estimates. The phi approach is an efficient method of achieving an accurate estimate of parameter(s) with good precision. Both the phi for individual parameter estimation and the overall phi for the estimation of model parameters led to optimal experimental design.
Conclusions:
Application of these approaches to the analyses of the results of the study was found useful in determining the best sampling design (from a series of two sampling times designs within a study) for efficient estimation of population pharmacokinetic parameters.