NONMEM Users Guide Part VI - PREDPP
Appendix.II. Another Example: Theophylline

NONMEM Users Guide Part VI - PREDPP

Appendix.II. Another Example: Theophylline

The population theophylline example of Guide I, section F, can be specified using PREDPP, as shown in this appendix. A NONMEM control stream, and PK and ERROR routines, are given on the following pages. A NM-TRAN control stream, using abbreviated PK and ERROR codes, is also given. The results are essentially identical to those given in Guide I, figures 76-83. Unlike the example of Guide I, the data set is not embedded in the control stream; it is found in a separate file, also given in this appendix. (This is unrelated to the fact that PREDPP is used.) A file stream, pointing to the data file, is also given.

This example uses ADVAN2, which implements an analytic computation for the one compartment linear model with first-order absorption. The same example can be handled using ADVAN6 and ADVAN7, although it is less efficient to use subroutines implementing "numerical" computations for general models when an analytic ADVAN for a specific model can be used. However, it may be instructive for the user to examine how all three ADVAN’s can be used for the same example, and to examine additional user-supplied codes to be used with these ADVAN’s. Therefore, this appendix also gives PK, MODEL, DES, and TOL routines to be used with ADVAN6, and PK and MODEL routines to be used with ADVAN7.

Finally, NM-TRAN control streams corresponding to the use of ADVAN6 and ADVAN7 with this example are also given. These use the very same data set as does the NONMEM control stream. However, the last two data item types, EVID and MDV, are ignored. Though NM-TRAN can always properly process these data item types, it can ignore them with this example.

Control Stream

FILE    FILESTREAM
PROB    THEOPHYLLINE   POPULATION DATA
DATA       1   0 144   7
ITEM       1   4   7  11   1
INDX       6   3   2
LABL      ID    DOSE    TIME      CP      WT    EVID     MDV
FORM
(5F10.0,2F2.0)
STRC       3   3   1               1   1
STRC       1   3
THCN       1
THTA          3.     .08     .04
LOWR          .1    .008    .004
UPPR          5.      .5      .9
BLST          6.    .005      .3   .0002    .006      .4
DIAG         .4
ESTM       0 450   3   5
COVR       0
TABL       0   1
TABL       4   1       2       5       3
SCAT       0   2
SCAT       3   9   1   1
SCAT       3  10   1   1

File Stream

DATA    DATAFILE
****

Data Set

         1      4.02      0.                 79.6 1 1
         1                0.         .74          0 0
         1                0.25      2.84          0 0
         1                0.57      6.57          0 0
         1                1.12     10.5           0 0
         1                2.02      9.66          0 0
         1                3.82      8.58          0 0
         1                5.1       8.36          0 0
         1                7.03      7.47          0 0
         1                9.05      6.89          0 0
         1               12.12      5.94          0 0
         1               24.37      3.28          0 0
         2      4.4       0.                 72.4 1 1
         2                0.        0.            0 0
         2                 .27      1.72          0 0
         2                 .52      7.91          0 0
         2                1.        8.31          0 0
         2                1.92      8.33          0 0
         2                3.5       6.85          0 0
         2                5.02      6.08          0 0
         2                7.03      5.4           0 0
         2                9.        4.55          0 0
         2               12.        3.01          0 0
         2               24.3        .90          0 0
         3      4.53      0.                 70.5 1 1
         3                0.        0.            0 0
         3                 .27      4.4           0 0
         3                 .58      6.9           0 0
         3                1.02      8.2           0 0
         3                2.02      7.8           0 0
         3                3.62      7.5           0 0
         3                5.08      6.2           0 0
         3                7.07      5.3           0 0
         3                9.        4.9           0 0
         3               12.15      3.7           0 0
         3               24.17      1.05          0 0
         4      4.4       0.                 72.7 1 1
         4                0.        0.            0 0
         4                 .35      1.89          0 0
         4                 .6       4.6           0 0
         4                1.07      8.6           0 0
         4                2.13      8.38          0 0
         4                3.5       7.54          0 0
         4                5.02      6.88          0 0
         4                7.02      5.78          0 0
         4                9.02      5.33          0 0
         4               11.98      4.19          0 0
         4               24.65      1.15          0 0
         5      5.86      0.                 54.6 1 1
         5                0.        0.            0 0
         5                 .3       2.02          0 0
         5                 .52      5.63          0 0
         5                1.       11.4           0 0
         5                2.02      9.33          0 0
         5                3.5       8.74          0 0
         5                5.02      7.56          0 0
         5                7.02      7.09          0 0
         5                9.1       5.9           0 0
         5               12.        4.37          0 0
         5               24.35      1.57          0 0
         6      4.        0.                 80.  1 1
         6                0.        0.            0 0
         6                 .27      1.29          0 0
         6                 .58      3.08          0 0
         6                1.15      6.44          0 0
         6                2.03      6.32          0 0
         6                3.57      5.53          0 0
         6                5.        4.94          0 0
         6                7.        4.02          0 0
         6                9.22      3.46          0 0
         6               12.1       2.78          0 0
         6               23.85       .92          0 0
         7      4.95      0.                 64.6 1 1
         7                0.         .15          0 0
         7                 .25       .85          0 0
         7                 .5       2.35          0 0
         7                1.02      5.02          0 0
         7                2.02      6.58          0 0
         7                3.48      7.09          0 0
         7                5.        6.66          0 0
         7                6.98      5.25          0 0
         7                9.        4.39          0 0
         7               12.05      3.53          0 0
         7               24.22      1.15          0 0
         8      4.53      0.                 70.5 1 1
         8                0.        0.            0 0
         8                 .25      3.05          0 0
         8                0.52      3.05          0 0
         8                 .98      7.31          0 0
         8                2.02      7.56          0 0
         8                3.53      6.59          0 0
         8                5.05      5.88          0 0
         8                7.15      4.73          0 0
         8                9.07      4.57          0 0
         8               12.1       3.            0 0
         8               24.12      1.25          0 0
         9      3.1       0.                 86.4 1 1
         9                0.        0.            0 0
         9                 .3       7.37          0 0
         9                 .63      9.03          0 0
         9                1.05      7.14          0 0
         9                2.02      6.33          0 0
         9                3.53      5.66          0 0
         9                5.02      5.67          0 0
         9                7.17      4.24          0 0
         9                8.8       4.11          0 0
         9               11.6       3.16          0 0
         9               24.43      1.12          0 0
        10      5.5       0.                 58.2 1 1
        10                0.         .24          0 0
        10                 .37      2.89          0 0
        10                 .77      5.22          0 0
        10                1.02      6.41          0 0
        10                2.05      7.83          0 0
        10                3.55     10.21          0 0
        10                5.05      9.18          0 0
        10                7.08      8.02          0 0
        10                9.38      7.14          0 0
        10               12.1       5.68          0 0
        10               23.7       2.42          0 0
        11      4.92      0.                 65.  1 1
        11                0.        0.            0 0
        11                 .25      4.86          0 0
        11                 .5       7.24          0 0
        11                 .98      8.            0 0
        11                1.98      6.81          0 0
        11                3.6       5.87          0 0
        11                5.02      5.22          0 0
        11                7.03      4.45          0 0
        11                9.03      3.62          0 0
        11               12.12      2.69          0 0
        11               24.08       .86          0 0
        12      5.3       0.                 60.5 1 1
        12                0.        0.            0 0
        12                 .25      1.25          0 0
        12                 .5       3.96          0 0
        12                1.        7.82          0 0
        12                2.        9.72          0 0
        12                3.52      9.75          0 0
        12                5.07      8.57          0 0
        12                7.07      6.59          0 0
        12                9.03      6.11          0 0
        12               12.05      4.57          0 0
        12               24.15      1.17          0 0

PK Routine To Be Used With ADVAN2

C  PK SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
C  USED WITH ADVAN2 AND TRANS1
C  CLEARANCE PROPORTIONAL TO WEIGHT
C  SCALING PARAMETER IS VOLUME/WEIGHT SINCE DOSE IS WEIGHT-ADJUSTED
      SUBROUTINE PK (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,IRGG,GG,NETAS)
      DIMENSION IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,*)
      DOUBLE PRECISION THETA,GG
      DOUBLE PRECISION WT
      IF (ICALL.LE.1) THEN

C SET UP IDEF ARRAY:

         IDEF(1,1)=-9

C ROW INDEX FOR SCALING PARAMETER FOR COMPT. 2

         IDEF(3,2)=4

C CALL PK ONCE PER INDIV. REC.

         IDEF(1,2)=1
      ELSE

C REGULAR CALL TO PK: C WEIGHT

         WT=EVTREC(1,5)

C ELIMINATION RATE CONSTANT

         GG(1,1)=THETA(2)
         GG(1,3)=1.

C ABSORPTION RATE CONSTANT

         GG(3,1)=THETA(1)
         GG(3,2)=1.

C SCALING

         GG(4,1)=THETA(3)/THETA(2)
         GG(4,3)=-GG(4,1)/THETA(2)
         GG(4,4)=1./(THETA(2)*WT)
      ENDIF
      RETURN
      END

ERROR Routine To Be Used With ADVAN2, ADVAN6, and ADVAN7

C  ERROR SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
      SUBROUTINE ERROR (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,F,G,HH)
      DIMENSION IDEF(*),THETA(*),EVTREC(IREV,*),INDXS(*),G(*),HH(*)
      DOUBLE PRECISION THETA,F,G,HH

C CALL ERROR ONLY ONCE

      IDEF(2)=2
      HH(1)=1.
      RETURN
      END

NM-TRAN Control Stream To Be Used With ADVAN2

$PROB  THEOPHYLLINE   POPULATION DATA
$INPUT      ID DOSE=AMT TIME CP=DV WT
$DATA       DATAFILE  (5F10.0)

$SUBROUTINES  ADVAN2

$PK
;THETA(1)=MEAN ABSORPTION RATE CONSTANT (1/HR)
;THETA(2)=MEAN ELIMINATION RATE CONSTANT (1/HR)
;THETA(3)=SLOPE OF CLEARANCE VS WEIGHT RELATIONSHIP (LITERS/HR/KG)
;SCALING PARAMETER=VOLUME/WT SINCE DOSE IS WEIGHT-ADJUSTED
   CALLFL=1
   KA=THETA(1)+ETA(1)
   K=THETA(2)+ETA(2)
   CL=THETA(3)*WT+ETA(3)
   SC=CL/K/WT

$THETA (.1,3,5) (.008,.08,.5) (.004,.04,.9) $OMEGA BLOCK(3) 6 .005 .0002 .3 .006 .4

$ERROR

   Y=F+EPS(1)

$SIGMA .4

$EST MAXEVAL=450 PRINT=5 $COV $TABLE ID DOSE WT TIME $SCAT (RES WRES) VS TIME BY ID

PK Routine To Be Used With ADVAN6 and ADVAN7

C  PK SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
C  USED WITH ADVAN6 AND ADVAN7, AND TRANS1
C  CLEARANCE PROPORTIONAL TO WEIGHT
C  SCALING PARAMETER IS VOLUME/WEIGHT SINCE DOSE IS WEIGHT-ADJUSTED
      SUBROUTINE PK (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,IRGG,GG,NETAS)
      DIMENSION IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,*)
      DOUBLE PRECISION THETA,GG
      DOUBLE PRECISION WT
      IF (ICALL.LE.1) THEN

C SET UP IDEF ARRAY:

         IDEF(1,1)=-9

C ROW INDEX FOR SCALING PARAMETER FOR COMPT. 2

         IDEF(3,2)=3

C CALL PK ONCE PER INDIV. REC.

         IDEF(1,2)=1
      ELSE

C REGULAR CALL TO PK: C WEIGHT

         WT=EVTREC(1,5)

C ELIMINATION RATE CONSTANT

         GG(2,1)=THETA(2)
         GG(2,3)=1.

C ABSORPTION RATE CONSTANT

         GG(1,1)=THETA(1)
         GG(1,2)=1.

C SCALING

         GG(3,1)=THETA(3)/THETA(2)
         GG(3,3)=-GG(3,1)/THETA(2)
         GG(3,4)=1./(THETA(2)*WT)
      ENDIF
      RETURN
      END

MODEL Routine To Be Used With ADVAN6

      SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)

C DEFINES A 1 COMPARTMENT MODEL WITH DRUG DEPOT COMPARTMENT C COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT

      DIMENSION IATT(IR,*),LINK(IR,*)
      INTEGER MOD(2,7)
      DATA MOD/

C INITIAL STATUS: OFF ON

     X 0,1,

C ON/OFF ALLOWED: YES NO

     X 1,0,

C DOSE ALLOWED: YES YES

     X 1,1,

C DEFAULT FOR OBSERVATIONS: NO YES

     X 0,1,

C DEFAULT FOR DOSES: YES NO

     X 1,0,

C FUNCTION (HIGH ORDER)

     X 4HDEPO,4HCENT,

C FUNCTION (LOW ORDER)

     X 4HT   ,4HRAL /
      NCM=2
      NPAR=2
      DO 10 J=1,7
      DO 10 I=1,NCM
   10 IATT(I,J)=MOD(I,J)
      RETURN
      END

DES Routine To Be Used With ADVAN6

C  DES SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
      SUBROUTINE DES (A,P,T,DADT,IR,DA,DP)
      DIMENSION A(*),P(*),DADT(*),DA(IR,*),DP(IR,*)
      DOUBLE PRECISION A,P,T,DADT,DA,DP
      DADT(1)=-P(1)*A(1)
      DADT(2)= P(1)*A(1)-P(2)*A(2)
      DA(1,1)=-P(1)
      DA(2,1)= P(1)
      DA(2,2)=-P(2)
      DP(1,1)=-A(1)
      DP(2,1)= A(1)
      DP(2,2)=-A(2)
      RETURN
      END

TOL Routine To Be Used With ADVAN6

C  TOL SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
      SUBROUTINE TOL (NRD)
      NRD=5
      RETURN
      END

NM-TRAN Control Stream To Be Used With ADVAN6

$PROB  THEOPHYLLINE   POPULATION DATA
$INPUT      ID DOSE=AMT TIME CP=DV WT
$DATA       DATAFILE  (5F10.0)

$SUBROUTINES  ADVAN6  TOL=5
$MODEL COMP=(DEPOT,INITIALOFF,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF)

$PK
;THETA(1)=MEAN ABSORPTION RATE CONSTANT (1/HR)
;THETA(2)=MEAN ELIMINATION RATE CONSTANT (1/HR)
;THETA(3)=SLOPE OF CLEARANCE VS WEIGHT RELATIONSHIP (LITERS/HR/KG)
;SCALING PARAMETER=VOLUME/WT SINCE DOSE IS WEIGHT-ADJUSTED
   CALLFL=1
   KA=THETA(1)+ETA(1)
   KE=THETA(2)+ETA(2)
   CL=THETA(3)*WT+ETA(3)
   S2=CL/KE/WT

$THETA (.1,3,5) (.008,.08,.5) (.004,.04,.9) $OMEGA BLOCK(3) 6 .005 .0002 .3 .006 .4

$DES

   DADT(1)=-KA*A(1)
   DADT(2)= KA*A(1)-KE*A(2)

$ERROR

   Y=F+EPS(1)

$SIGMA .4

$EST MAXEVAL=450 PRINT=5 $COV $TABLE ID DOSE WT TIME $SCAT (RES WRES) VS TIME BY ID

MODEL Routine To Be Used With ADVAN7

      SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)

C DEFINES A 1 COMPARTMENT LINEAR MODEL WITH FIRST-ORDER ABSORPTION C COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT

      DIMENSION IATT(IR,*),LINK(IR,*)
      INTEGER MOD(2,7)
      DATA MOD/

C INITIAL STATUS: OFF ON

     X 0,1,

C ON/OFF ALLOWED: YES NO

     X 1,0,

C DOSE ALLOWED: YES YES

     X 1,1,

C DEFAULT FOR OBSERVATIONS: NO YES

     X 0,1,

C DEFAULT FOR DOSES: YES NO

     X 1,0,

C FUNCTION (HIGH ORDER)

     X 4HDEPO,4HCENT,

C FUNCTION (LOW ORDER)

     X 4HT   ,4HRAL /
      NCM=2
      NPAR=2
      DO 10 J=1,7
      DO 10 I=1,NCM
   10 IATT(I,J)=MOD(I,J)

C SET LINK: C K12

      LINK(1,2)=1

C K20

      LINK(2,3)=2
      RETURN
      END

NM-TRAN Control Stream To Be Used With ADVAN7

$PROB  THEOPHYLLINE   POPULATION DATA
$INPUT      ID DOSE=AMT TIME CP=DV WT
$DATA       DATAFILE  (5F10.0)

$SUBROUTINES  ADVAN7
$MODEL COMP=(DEPOT,INITIALOFF,DEFDOSE) COMP=(CENTRAL,DEFOBS,NOOFF)

$PK
;THETA(1)=MEAN ABSORPTION RATE CONSTANT (1/HR)
;THETA(2)=MEAN ELIMINATION RATE CONSTANT (1/HR)
;THETA(3)=SLOPE OF CLEARANCE VS WEIGHT RELATIONSHIP (LITERS/HR/KG)
;SCALING PARAMETER=VOLUME/WT SINCE DOSE IS WEIGHT-ADJUSTED
   CALLFL=1
   K12=THETA(1)+ETA(1)
   K20=THETA(2)+ETA(2)
   CL=THETA(3)*WT+ETA(3)
   S2=CL/K20/WT

$THETA (.1,3,5) (.008,.08,.5) (.004,.04,.9) $OMEGA BLOCK(3) 6 .005 .0002 .3 .006 .4

$ERROR

   Y=F+EPS(1)

$SIGMA .4

$EST MAXEVAL=450 PRINT=5 $COV $TABLE ID DOSE WT TIME $SCAT (RES WRES) VS TIME BY ID

TOP
TABLE OF CONTENTS
NEXT APPENDIX ...