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| TIME AFTER DOSE (TAD) EXAMPLE |
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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.
Two versions of the code are given.
VERSION I
Code to compute TADE ("TAD Effective"). The time that the dose
enters the system is used, which is the time the dose was admin-
istered plus ALAG.
VERSION II
Code to compute TADA ("TAD Administered"). The time that the dose
was administered is used, and ALAG is ignored.
If PDxPop is used or any other software that looks for TAD in the ta-
ble, specify TAD=TADA or TAD=TADE in the $TABLE record.
$PROB TIME AFTER DOSE (Based on RUN# 705 nonmem coding challenge #1)
; This example shows how Time After Dose can be computed.
; It contains two independent versions of the computation.
; Version I computes TADE (Time After Dose Effective)
; If there is absorption lag, TADE is the Time after the lagged dose,
; that is, the time the dose actually enters the sysem.
; Version II computes TADA (Time After Dose Administered)
; Absorption lag is ignored.
;
; As of Dec. 17, 2018
;
$INPUT C ID TIME DV AMT WT AGE CRCL SMK ADDL II EVID DROP
$DATA 706.csv IGNORE=C
$SUBROUTINE ADVAN2 TRANS2
$PK
;
ALAG1=0 ; ALAG1 is 0 for this example, but could be set to some other
; value. With ALAG1=0, either version can be used.
; However, VERSION I IS simpler and is preferred.
;
; VERSION I: CODE TO COMPUTE TADE = TAD EFFECTIVE (USE ALAG)
; PREDPP KEEPS TRACK INITIATING AND IMPLIED DOSES, AND COMPUTES DOSTIM
IF (NEWIND.LT.2.OR.EVID.EQ.3) THEN
TDOSE=-999 ; TIME OF MOST RECENT DOSE. -999 IF NO PREVIOUS DOSE.
TADE=0.0 ; TIME AFTER DOSE EFFECTIVE
ENDIF
IF (EVID.EQ.1.AND.ALAG1.EQ.0.OR.EVID.EQ.4.AND.ALAG1.EQ.0) TDOSE=TIME
IF (DOSTIM.GT.0) TDOSE=DOSTIM
IF (TDOSE.GT.-999) TADE=TIME-TDOSE
; If no ALAG and no ADDL doses, the above three lines become:
; IF (EVID.EQ.1.OR.EVID.EQ.4) TDOSE=TIME
; IF (TDOSE.GT.-999) TADE=TIME-TDOSE
;
; End of VERSION I
; VERSION II: CODE TO COMPUTE TADA = TAD ADMINISTERED (IGNORES ALAG)
; IF ALAG>0, PREDPP's DOSTIM CANNOT BE USED FOR TADA
; THE ABBREVIATED CODE MUST KEEP TRACK OF INITIATING AND IMPLIED DOSES.
; THIS CODE IS SIMILAR TO tip4-new-general-01-31-18.txt
IF (NEWIND.LT.2.OR.EVID.EQ.3) THEN
TDOSA=-999 ; TIME OF MOST RECENT DOSE. -999 IF NO PREVIOUS DOSE.
TADA=0.0 ; TIME AFTER DOSE ADMINISTERED
ENDIF
IF (DOSTIM==0) THEN ; IGNORE NON-EVENT DOSE TIMES (DOSTIM>0)
IF(EVID.EQ.1.OR.EVID.EQ.4) THEN ; NEW DOSE EVENT RECORD
TADA=0.0
DIV=II
TDOSA=TIME
TLAST=TDOSA+ADDL*II ; TLAST IS THE TIME OF THE FINAL IMPLIED DOSE
ENDIF
IF (TDOSA.GE.0.AND.EVID.NE.1.AND.EVID.NE.4) THEN ; THERE WAS AN EARLIER DOSE
IF (TIME>TLAST) THEN
TADA=TIME-TLAST ; CURRENT TIME IS PAST THE TIME OF THE FINAL IMPLIED DOSE
ELSE
DIFF=TIME-TDOSA
TADA=MOD(DIFF,DIV) ; COMPUTES TIME OF THE MOST RECENT IMPLIED DOSE
ENDIF
ENDIF ; NOT A DOSE
ENDIF ; END OF DOSTIM==0
;
; End of VERSION II
CL=THETA(1)*EXP(ETA(1))
TVV=THETA(2)
V=TVV*EXP(ETA(2))
TVKA=THETA(3)
KA=TVKA*EXP(ETA(3))
S2=V
$THETA
(0, 10)
(0, 100)
(0, 0.5)
$ERROR
Y=F+ERR(1)
IPRED=F
$OMEGA
0.04 ;[P] INTERIND VAR IN CL
0.04 ;[P] INTERIND VAR IN V
0.04 ;[P] INTERIND VAR IN KA
$SIGMA
0.2 ;[A] ADDITIVE COMPONENT
$EST MAXEVAL=0 PRINT=2 NOABORT ;POSTHOC
;
; If PDxPop is used or any other software that looks for TAD in the table, specify
; TAD=TADA or TAD=TADE in the $TABLE record
$TABLE ID TIME EVID TDOSA TADA TDOSE TADE IPRED NOAPPEND NOPRINT ONEHEADER
FILE=tadexa.tab FORMAT=SF11.7
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
0,1,0,0,0,58.4,51,4.49,1,0,0,2,0
0,1,0.1,0,500,58.4,51,4.49,1,1,24,1,0
0,1,1.1,1.67538,0,58.4,51,4.49,1,0,0,0,0
0,1,4.1,2.79283,0,58.4,51,4.49,1,0,0,0,0
0,1,10.1,0.583263,0,58.4,51,4.49,1,0,0,0,0
0,1,24.1,0.146255,0,58.4,51,4.49,1,0,0,0,0
0,1,25.1,1.67538,0,58.4,51,4.49,1,0,0,0,0
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
https://nonmem.iconplc.com/nonmem/tips
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
nonmem.
tip3-revised-01-31-18.txt
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.
tip4-revised-01-31-18.txt
Uses Fortran suboutine INFN and equivalent $INFN code. The
datafile is 706.csv.
tip4update-revised-01-31-18.txt
Uses DOSTIM.
The original versions are still in the tips directory with
new names that include the original dates.
tip3-2-25-02.txt
tip4-3-04-02.txt
tip4update-10-11-13.txt
REFERENCES: None
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