NONMEM Users Guide Part VI - PREDPP

Appendix.III. One-Dimensional Format for IDEF of PK

In the PK routine IDEF is either a one- or two-dimensional array. The two-dimensional format is the most convenient one to use, and it is described in section III.G. With PREDPP versions I and II only the one-dimensional format is allowed. This format is retained in Version III for the convenience of previous users, and it is described in this appendix. However, if IDEF is to convey information not applicable in PREDPP versions I and II, the two-dimensional format must be used. For example, if an absorption lag time is being modeled, this information must be conveyed by the two-dimensional formatted IDEF. When using the one-dimensional format, IDEF should be declared IDEF(*) in the PK DIMENSION statement.

With each kinetic model there corresponds an ordered list of all possible additional PK parameters. So, for example, with the one compartment linear model the list is: S1, S2, F1, R1, D1, , X, where 1 and 2 are numbers referring to the central and output compartments, respectively. Both compartments can be observed, and therefore the amounts in each of them can be scaled. However, only the central compartment can be a dose compartment, and so only that compartment has an associated bioavailability fraction, rate parameter, and duration parameter. See section VII.C for the lists corresponding to the various models. The elements of the list are numbered sequentially. In the above example, S1 is numbered 1, and X is numbered 7.

Just as typical/subject-specific values and -derivatives for each of the basic PK parameters are stored in some row of the GG array, so are the typical/subject-specific values and -derivatives for each of the additional PK parameters. The rows can be assigned somewhat arbitrarily. If the user chooses to model the Nth additional PK parameter, then IDEF(N) should be set to the index of the assigned row, called the row index.

There is a number, , that is the largest number of basic parameters permitted with the selected kinetic model. This number is either set in the selected ADVAN subroutine (see section VII.C) or set by the user via the MODEL subroutine (see section VI.B). A row index M assigned to an additional PK parameter must be a number greater than , but no greater than 30. Consider, for example, the one compartment linear model, with one basic PK parameter: rate constant of elimination. (This parameterization is implemented via TRANS1.) From section VII.C.1 it may be seen that . If S1 is to be modeled, then one can set IDEF(1)=3. If S2 is also to be modeled, then one can set IDEF(2)=4.

The row indices of the additional PK parameters must be consecutive integers beginning with , with no integers skipped, as in the above example. However, one is not restricted to preserving an increasing monotonic relationship between the numbers of the parameters and their row indices. So, one can just as well set IDEF(1)=4 and IDEF(2)=3. Nor is one restricted from using a row index more than once. So, one can set IDEF(1)=IDEF(2)=3, though usually there is no need to do this. (IDEF(1)=IDEF(2)=4 is not allowed, though, since then the row index 3 is skipped.)

Often, none of the basic or additional parameters depend on concomitant variables whose values vary within an individual record, i.e. vary over time. In this situation, the information output by PK, i.e. the GG array, is the same for each event record of an individual record (for fixed THETA and ETA). If PREDPP knows that this situation holds, it can save considerable computation time; it will call PK only once per individual record, with the first event record only (for any given values of the THETA and ETA arrays). The user can implement this calling-protocol by setting , where is the total possible number of additional PK parameters (the last number in the list of additional parameters).

The default calling-protocol of PREDPP Version II can be implemented by setting . Note, though, that in this case, must be explicitly set to 0. Even when is 0 or 1, a call to PK with any given event record can be forced with the use of the CALL data item (see Section V.J).

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