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RE: Time After Dose example in help/html

From: Mats Karlsson <Mats.Karlsson>
Date: Wed, 28 Nov 2018 18:31:19 +0000

Dear Alison,

I have always considered the time-after-dose variable to provide values related to when the dose was administered, not that time plus any ALAG. If I read your code right, you propose to do it as administration time + ALAG. I would argue that it is more valuable to have the former.

Best regards,

-----Original Message-----
From: owner-nmusers> On Behalf Of Alison Boeckmann
Sent: den 27 november 2018 19:59
To: nmusers bf <>
Subject: [NMusers] Time After Dose example in help/html

Time after dose (TAD) is useful to some NONMEM and PDxPop users.
PREDPP does not compute it. It has to be computed by the user and listed in the table file. Depending on the kinds of doses, this may be difficult. There are several sources of advice:

(1) tip3 and tip4 and tip4update in the Nonmem tip directory
These were revised in 01-31-18.
All the tips should work correctly with NONMEM 7, but are of limited usefulness because they are not general.

(2) Over the years, users have asked for help or volunteered their own solutions to the problem via nmusers email. The code is not consistent, and some users may still find it difficult to write the code for some kinds of doses.

(3) With nonmem 7.4.2, there is a new example TADEXA in the help/html directories. It is code that can compute TAD with both ALAG and multiple dosing using ADDL. It also contains notes that discuss the tips.

An improved version of tadexa is included in this email. It has improved comments and notes, and more consistent use of the data files. The abbreviated code is not changed.

I am writing to encourage users to help improve tadexa in hopes that TAD can be computed identically by all users, using standard code which is documented in the help/html files.

If you have code that computes TAD for your data, can you try the code from tadexa and see if the values of TAD match?
Please send an email to to report a match, or to report a discrepancy in values of TAD. We will try to resolve the discrepancy.

Alison Boeckmann
Nov 18, 2018

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 This fully-worked out example shows how Time After Dose (TAD) may be computed in $PK abbreviated code. It works with transient and steady- state doses, and also with additional and lagged doses.

 It is based on suggestions from the NONMEM tips directory but is not identical to any of them. See Note 8 for a discussion of the tips.

 $PROB Based on RUN# 705 nonmem coding challenge #1 ; As of Nov. 1, 2018 $INPUT C ID TIME DV AMT WT AGE CRCL SMK ADDL II EVID DROP $DATA 706.csv IGNORE=C $SUBROUTINE ADVAN2 TRANS2 $PK ; initialize for new individual or reset record IF (NEWIND.LT.2.OR.EVID.EQ.3) THEN
  TDOS=-999 ; Time of most recent dose. -999 if no previous dose.
  TAD=0 ; Time After Dose
 ALAG1=0 ; ALAG1 is 0 for this example, but could be set to some other value ; ; Save TDOS (time of last dose) and compute TAD (time after dose) ; General case: ADDL doses and ALAG may be modelled IF (EVID.EQ.1.and.ALAG1.EQ.0.OR.EVID.EQ.4.and.ALAG1.EQ.0) TDOS=TIME IF (DOSTIM.GT.0) TDOS=DOSTIM IF (TDOS.GT.-999) TAD=TIME-TDOS

 ; If no ALAG or ADDL doses, the above three lines become:

   (0, 10)
   (0, 100)
   (0, 0.5)
   0.04 ;[P] INTERIND VAR IN V

 The data for the first subject in 706.csv is:

 C,Data Desc: test of TAD for ADDL,,,,,,,,,, C,ID,TIME,DV,AMT,WT,AGE,CRCL,SMK,ADDL,II,EVID,TAD

 The original data set 704.csv is embedded in tip3-2-25-02.txt. Data
 set 706.csv can be found in the tips directory. It was created from 704.csv by appending an extra column, TAD, whose values are zero.
 $INFN code in the tips assign values to the TAD data item (see Note 8). The code in the present example does not use the TAD data item (DROP is listed in $INPUT). Instead, TAD is a user-defined variable listed in MODULE NMPRD4 from which its values may be displayed in a table file.

 Note 1.
      It is assumed that TAD is displayed in tables for the purpose of
      graphical display of the data. It is not a random variable, and
      is not intended to be part of the prediction model.

 Note 2.
      If there are non-dose records prior to the first dose record of
      the Individual record, TAD is set to zero for these records.
      This is an arbitrary convention; the user could use different
      values, especially if these conditions might signal an error in
      the data set.

 Note 3.
      ALAG1 is used in the example, but a different dosing compartment
      could be used, e.g., ALAG2 for doses into compartment 2. The
      code would need modification to compute TAD for doses into two or
      more compartments.

 Note 4.
      This code can handle random DOSTIM (Eta on ALAG or ETA on mod-
      elled duration or rate.)

 Note 5.
      The code does not use INFN. The information is developed with
      passes through the data set at ICALL=2, in which NONMEM calls
      PREDPP. During a pass in which INFN is called, PREDPP is not
      called. The abbreviated code would have to account for additional
      and lagged dose times.

 Note 6.
      TDOS=-999 until the first dose. TDOS=0 when the first dose is at
      TIME 0. This makes it possible to dispense with a flag variable
      whose only function is to say "a dose has occurred". If there
      are negative time values in the data set and any time value is
      smaller than -999, then

 Note 7.
      The code is intended to compute TAD for multiple individual doses
      or one initiating dose. (An initiating dose has ADDL>0,II>0).

 Note 8.
      Changes were made to tip3, tip4, and tip4update in the NONMEM
      tips directory. See tips in

      In each case, the name of the revised tip contains 01-31-18 and
      supercedes the original. Although the tips were revised as part
      of the nonmem 7.4.2 release they apply to previous versions of

           The original version, tip3-2-25-02.txt, provides a data file
           704.csv and a simple model. The revised version provides
           improved code, similar to the code in tadexa.exa.

           Uses Fortran suboutine INFN and equivalent $INFN code. The
           datafile is 706.csv.

           Uses DOSTIM.

           The original versions are still in the tips directory with
           new names that include the original dates.



  Alison Boeckmann

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Received on Wed Nov 28 2018 - 13:31:19 EST

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