RE: Time After Dose example in help/html

-----Original Message----- From: [email protected] <[email protected]> On Behalf Of Alison Boeckmann Sent: den 18 december 2018 19:29 To: [email protected]; ajbf <[email protected]>; Robert Bauer <[email protected]> Subject: [NMusers] Time After Dose example in help/html The following email supercedes the email of November 27, 2018. At the suggestion of Mats Karlsson, it also computes TADA, which is TAD relative to the time when the dose was administered, ignoring ALAG. The original variable TAD is now called TADE, which is TAD relative to the effective time of the dose, including ALAG. ============ ` 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 https://nonmem.iconplc.com/nonmem/tips 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. Two versions of the computation are included. Version I computes TADE ("TAD Effective"). The time that the dose enters the system is used, which is the time the dose was administered plus ALAG. VERSION II computes TADA ("TAD Administered"). The time that the dose was administered is used, and ALAG is ignored. 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 [email protected] to report a match, or to report a discrepancy in values of TAD. We will try to resolve the discrepancy. Alison Boeckmann Dec 17, 2018 =========== +--------------------------------------------------------------------+ | | | TIME AFTER DOSE (TAD) EXAMPLE | | | +--------------------------------------------------------------------+ 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 -- Alison Boeckmann [email protected] När du har kontakt med oss på Uppsala universitet med e-post så innebär det att vi behandlar dina personuppgifter. För att läsa mer om hur vi gör det kan du läsa här: http://www.uu.se/om-uu/dataskydd-personuppgifter/ E-mailing Uppsala University means that we will process your personal data. For more information on how this is performed, please read here: http://www.uu.se/en/about-uu/data-protection-policy