Population pharmacokinetics framework

Over the past 25 years a variety of methods have been proposed for the characterization of the population pharmacokinetics of drugs. In this chapter, the statistical framework for estimating population pharmacokinetics in terms of individual and population models is discussed as a prelude to discussing some of the methods used in estimating population pharmacokinetics. In doing so we have adopted a user-friendly approach described previously (14). The goals of a PPK analysis and the data type (1) will determine the method selected for the analysis. 

The framework for the mixed effect modeling approach to population pharmacokinetic analysis can be dehned from the same two/three-stage approach perspective. For the f = 1,. .., n individuals in a population of interest, letXy,7 = rij represent the design points on which the responses are observed. In the pharmacokinetic setting, Xij are typically the sampling time points and are the observed concentrations in the biologic matrix of interest (usually plasma or blood). Hence, the pharmacokinetic response can be described by... 

Nonlinear mixed-effects modeling methods as applied to pharmacokinetic-dynamic data are operational tools able to perform population analyses [461]. In the basic formulation of the model, it is recognized that the overall variability in the measured response in a sample of individuals, which cannot be explained by the pharmacokinetic-dynamic model, reflects both interindividual dispersion in kinetics and residual variation, the latter including intraindividual variability and measurement error. The observed response of an individual within the framework of a population nonlinear mixed-effects regression model can be described as... 

Unlike the individual model discussed above, a more elaborate statistical model is required to deal with sparse pharmacokinetic data. In formulating the model, it is recognized that overall variability in the measured (response) data in a sample of individuals reflects both measurement error and intersubject variability. The observed response (e.g., concentration) in an individual within the framework of population... 

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