118  PREDPP

Introduction to NONMEM Version VI

1. There is a new feature: model event times. These are additional PK parameters MTIME(i) defined in the PK routine or $PK block. A model event time, like an absorption lag time, defines a time to which the system is advanced, but whose value usually cannot be known in advance. When the time is reached, certain indicator variables are set and a call to PK is made. At this call PK, DES, AES and ERROR can use the indicator variables to change some aspect of the system, e.g., a term in a differential equation, or the rate of an infusion. Thus, a model event time can be used e.g. to mark the time at which the gall bladder begins to empty. A model event time could be implemented by using an absorption lag time, and this is what has been done until now, but doing this is somewhat clumsy. There may be up to PCT model event times, where PCT is a new installation parameter defined in SIZES. Its default value is 30.

(See the MTIME and $PK and PRDPK1 and PRDPK2 Help Items and the MODEL TIME Example)

2. There is a new variable A_0FLG - the “compartment initialization flag” - in a new PREDPP read-only common PROCMC. When event records are passed to routine PK, PREDPP sets A_0FLG to 1 with the first event record of an individual record or with any reset record, and to 0 with all other records. When A_0FLG=1, compartment amounts have been initialized to zero, i.e. the state vector A (and its η-derivatives) has been set to zero, but PK may reinitialize the compartment amounts to nonzero values by resetting the state vector (and its η-derivatives) to such values (in a new PREDPP-PK common PRDPK3).

(See the $PK and PROCMC and PRDPK3 and COMPARTMENT INITIALIZATION BLOCK Help Items.)

A_0FLG is a reserved variable in $PK. See section 4.2 below for further discussion as to how to initialize compartment amounts.

3. With the PK routine, the compartment amounts (and their η-derivatives) may be found in PREDPP read-only common PROCM4. These are the latest computed compartment amounts. That is, they are the amounts at the previous event time, or if at a later time (but before the event time for which it may be that PK is being called) a lagged or additional dose was given, or a regular infusion was terminated, or an event occurred at a modeled event time, then they are the amounts at the latest such time. Now, with Version VI, there is a new PREDPP read-only common PROCM9 in which the time at which these compartment amounts are in fact computed may be found.

(See the PROCM4 and PROCM9 Help Items.)

4. When the value of the compartment data item (CMT) is n+1, where n is the total number of compartments in the kinetic system, the data item designates the (special additional) output compartment. With Version VI, this can also be done with the value 100, which is useful when n changes from run to run.

(See the CMT Help Item.)

1 PREDPP: New Feature: Initial Steady State

With NONMEM VI 2.0, PREDPP may be requested to compute steady state as the initial condition for a model. This feature is for use with general non-linear models (ADVAN6, ADVAN8, ADVAN9), when endogenous doses are present in the differential equations. Previously, the only way to do this was by using a dose event record having SS>0, AMT=0, RATE=0. With this feature, the initial condition is computed prior to the first event record (and after a reset event record) exactly as if such a dose record were present. It is not necessary to include the a dose record or, indeed, to define the data item SS, AMT or RATE. There is a new common PRDPK4.

(See the PRDPK4 and ADVAN6 ADVAN8 and ADVAN9 and $MODEL Help Items.)

2 PREDPP: New in SIZES: MAXFCN

Routines ADVAN6, ADVAN8, ADVAN9, and SS6 use a variable MAXFCN to specify the maximum number of calls to FCN1 (ADVAN6, ADVAN8, SS6) or RES (ADVAN9) during an integration interval. Previously, this variable was set to 100000 in the routines themselves, and the user could supply a larger value by setting IMAX in PRCOMG (e.g., by using verbatim code in the $PK block). Now, MAXFCN is set in SIZES, and is given a larger value 1000000. If an even larger value is desired, SIZES may be changed and PREDPP recompiled, or IMAX in PRCOMG may be set to the larger value using verbatim code.

Old verbatim code that changes IMAX will work as it did with previous releases, but, if IMAX is being set to 1000000, the verbatim code is no longer needed.

(See the SIZES and PRCOMG Help Items.)