Before we continue to the popPK models, let us review how NONMEM treats variability in the data.

We saw that when the data are population, In NONMEM the inter-individual variability refers to the unexplained difference between individuals' parameter values and the typical values in the population. It is described in NM-TRAN using ETA(n) variables. PRED describes the effect of these variables to NONMEM via the partial derivatives in the G array. The variance of these variables is given in the OMEGA matrix.

Random intra-individual variability refers to unexplained (residual) error in a model (the difference between observed and predicted values). It is described in NM-TRAN using EPS(n) or ERR(n) variables. PRED describes the effect of these variables to NONMEM via the partial derivatives in the H array. The variance of these variables is given in the SIGMA matrix.

We did not cover when the data are single-subject, but here we point the following. In this case, random inter-individual variability refers unexplained (residual) error in a model (the difference between observed and predicted values). This, despite the fact that data may come from a single subject, is because each observation is placed into a separate individual record, and because only level-one random effects are needed to describe it. It is described in NM-TRAN using ERR(n) or ETA(n) variables. PRED describes the effect of these vari- ables to NONMEM via the partial derivatives in the G array. The variance of these variables is given in the OMEGA matrix.

However, when the data are in fact from a single subject, and when there is no need to use NONMEM terminology, then users often associate the ETA(n) and OMEGA with intra-individual variability, which corresponds to their experimental point of view.

Recall that NONMEM provides PRED routine for users to specify the statistical structure and the nonlinear dynamics of a model. The PRED routine can become very complicated , especially when ordinary differential equations are involved. To alleviate the coding burden NONMEM provides a suite of PRED routines called PREDPP (PRED Population Pharmacokinetics) for the population pharmacokinetics analysis. PREDPP contains a number of basic kinetic models for user to select. For example: if the user is interested in a common compartment linear model, he chooses PREDPP subroutines such as ADVAN1, ADVAN2, and ADVAN3, and skip hand-coding the PRED routine. In this part, we go through some PK models and PK/PD models using PREDPP routines.