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.
FCON Stream
FILE FSTREAM
PROB THEOPHYLLINE POPULATION DATA
DATA 1 0 144 7 0 0 0 0
ITEM 1 4 7 11 1 0 0 0 0 0 0 0 0 0 0
INDX 6 3 2 0 0 0 0 0 0 0 0
XVID 0 0 0 0 0
MSDT 0.00000000000000E+000
LABL ID, DOSE TIME, CP
WT, EVID
MDV
LBW1 IWRS,IPRD
IRS,NPRED
NRES,NWRES
NIWRES,NIPRED
NIRES,CPRED
CRES,CWRES
CIWRES,CIPRED
CIRES,PREDI
RESI,WRESI
IWRESI,IPREDI
IRESI,CPREDI
CRESI,CWRESI
CIWRESI,CIPREDI
CIRESI,EPRED
ERES,EWRES
EIWRES,EIPRED
EIRES,NPDE
ECWRES,NPD
OBJI
LRES SIGMA LTHT LETA LEPS FORM (5F10.0,2F2.0) STRC 3 3 1 0 0
0 1 1 0 STRC 1 3 THCN 1 0 0 0 THTA 3.000000000000000E+00,
8.000000000000000E-02, 4.000000000000000E-02 LOWR
1.000000000000000E-01, 8.000000000000000E-03,
4.000000000000000E-03 UPPR 5.000000000000000E+00,
5.000000000000000E-01, 9.000000000000000E-01 BLST
6.000000000000000E+00, 5.000000000000000E-03,
3.000000000000000E-01
2.000000000000000E-04, 6.000000000000000E-03,
4.000000000000000E-01
DIAG 4.000000000000000E-01 DFLT -1 ESTM 0 450 3 5 0 0 0 0 0
0 0 0 0 0 0 0 0 0
0 0 0 0 -1 -1 0 0 0
BEST -100 -100 -100 -100 -100.00000 -100
-100 -100 -100.00000 -2147483647 -100 -100
-100 -100.00000 -100 -100-0.10000E+03 -100
-100 -100 0 -100 -100 -100.00000
-100 -100 -100 -100-0.10000E+03-0.10000E+03
-100 -100 1 -100 -100
-100 -100 -2147483647 -100 -100-0.10000E+03
-100-0.10000E+03-0.10000E+03 -100 0 -100
-100 -100 -100-0.10000E+03-0.10000000E+03 -100
-100 -100 -100 -100-0.10000000E+03-0.10000000E+03
-0.10000000E+03-0.10000000E+03-0.10000000E+03-0.10000000E+03-0.10000000E+03-0.10000000E+03
-0.10000000E+03-0.10000000+301-0.10000000+301
-100-100-100-100-100-100
-100 -100 -100-0.10000000E+03-0.10000000E+03-0.10000000E+03
-100 -100 -100-0.10000000E+03-0.10000000E+03-100
-100 -100 -100 -100
BFIL BDLM BMUM BGRD ORDR PFIL -100 FFIL 0 COVR 0 0 0 0 0 0 1
0 0 COVT -1 -1 -1 -1 0 0 -1 -1 -1 -1 -1 -1 -1-1-1TOS
-1 -1 -1-0.10000E+03-0.10000E+03-0.10000E+03
CPAR -1 TABL 1 1 PPAR -1
TABL 1 4 1 0 2 0 5 0 3 0
0 0 0 0 0 0 0 0-1 0
FRML FRMR FETA SCAT 1 2 SCAT 3 9 1 1 0 0 0 0 0
0 0 0 -1
SCAT 3 10 1 1 0 0 0 0 0
0 0 0 -1
File Stream
DATA FDATA ****
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
SUBROUTINE PK(ICALL,IDEF,THETA,IREV,EVTREC,NVNT,INDXS,IRGG,GG,NETAS)
! PK SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA !
USED WITH ADVAN2 AND TRANS1 ! CLEARANCE PROPORTIONAL TO
WEIGHT ! SCALING PARAMETER IS VOLUME/WEIGHT SINCE DOSE IS
WEIGHT-ADJUSTED
USE NMPRD4P
USE SIZES, ONLY: DPSIZE,ISIZE
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
USE NMPRD_REAL,ONLY: ETA,EPS
USE NMPRD_INT, ONLY:
MSEC=>ISECDER,MFIRST=>IFRSTDER,COMACT,COMSAV,IFIRSTEM
USE NMPRD_INT, ONLY: MDVRES,ETASXI,NPDE_MODE,NOFIRSTDERCODE
USE NMPRD_REAL, ONLY: DV_LOQ
USE NMPRD_INT, ONLY: IQUIT
USE PROCM_INT, ONLY: NEWIND=>PNEWIF
USE NMBAYES_REAL, ONLY: LDF
IMPLICIT REAL(KIND=DPSIZE) (A-Z)
REAL(KIND=DPSIZE) :: EVTREC
SAVE
INTEGER(KIND=ISIZE) :: FIRSTEM
INTEGER(KIND=ISIZE) :: ICALL,IDEF,IREV,NVNT,INDXS,IRGG,NETAS
DIMENSION ::
IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,GPKD+1,*)
FIRSTEM=IFIRSTEM
IF (ICALL <= 1) THEN
CALL ASSOCNMPRD4
! SET UP IDEF ARRAY:
IDEF( 1,0001)= -9
! CALL PK ONCE PER INDIV. REC.
IDEF( 1,0002)= 1
IDEF( 1,0003)= 0
IDEF( 1,0004)= 0
IDEF( 2,0003)= 0
IDEF( 2,0004)= 0
! ROW INDEX FOR SCALING PARAMETER FOR COMPT. 2
IDEF( 3,0002)= 4
CALL GETETA(ETA)
IF (IQUIT == 1) RETURN
RETURN
ENDIF
IF (NEWIND /= 2) THEN
IF (ICALL == 4) THEN
CALL SIMETA(ETA)
ELSE
CALL GETETA(ETA)
ENDIF
IF (IQUIT == 1) RETURN
ENDIF
! level 0
! REGULAR CALL TO PK: ! WEIGHT
WT=EVTREC(NVNT,005)
KA=THETA(001)+ETA(001)
K=THETA(002)+ETA(002)
CL=THETA(003)*WT+ETA(003)
SC=CL/K/WT
IF (FIRSTEM == 1) THEN
! A000031 = DERIVATIVE OF KA W.R.T. ETA(001)
A000031=1.D0
! A000032 = DERIVATIVE OF K W.R.T. ETA(002)
A000032=1.D0
B000001=1.D0/K/WT
! A000034 = DERIVATIVE OF SC W.R.T. ETA(003)
A000034=B000001
B000002=-CL/K/K/WT
! A000035 = DERIVATIVE OF SC W.R.T. ETA(002)
A000035=B000002*A000032
! ELIMINATION RATE CONSTANT
GG(0001,1,1)=K
GG(0001,0003,1)=A000032
! ABSORPTION RATE CONSTANT
GG(0003,1,1)=KA
GG(0003,0002,1)=A000031
! SCALING
GG(0004,1,1)=SC
GG(0004,0003,1)=A000035
GG(0004,0004,1)=A000034
ELSE
GG(0001,1,1)=K
GG(0003,1,1)=KA
GG(0004,1,1)=SC
ENDIF
IF (MSEC == 1) THEN
B000004=-1.D0/K/K/WT
! A000037 = DERIVATIVE OF B000001 W.R.T. ETA(002)
A000037=B000004*A000032
B000005=-1.D0/K/K/WT
B000006=CL/K/K/K/WT
! A000039 = DERIVATIVE OF B000002 W.R.T. ETA(002)
A000039=B000006*A000032
B000007=CL/K/K/K/WT
! A000040 = DERIVATIVE OF B000002 W.R.T. ETA(002)
A000040=B000007*A000032+A000039
! A000041 = DERIVATIVE OF A000035 W.R.T. ETA(002)
A000041=A000032*A000040
! A000042 = DERIVATIVE OF A000035 W.R.T. ETA(003)
A000042=A000032*B000005
GG(0004,0003,0003)=A000041
GG(0004,0004,0003)=A000042
ENDIF
RETURN
END
ERROR Routine To Be Used With ADVAN2, ADVAN6, and ADVAN7
! ERROR SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA SUBROUTINE ERROR (ICALL,IDEF,THETA,IREV,EVTREC,NVNT,INDXS,F,G,HH)
USE NMPRD4P
USE SIZES, ONLY: DPSIZE,ISIZE
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
USE NMPRD_REAL,ONLY: ETA,EPS
USE NMPRD_INT, ONLY: MSEC=>ISECDER,MFIRST=>IFRSTDER,IQUIT,IFIRSTEM
USE NMPRD_INT, ONLY: MDVRES,ETASXI,NPDE_MODE,NOFIRSTDERCODE
USE NMPRD_REAL, ONLY: DV_LOQ
USE NMPRD_INT, ONLY: NEWL2
USE PROCM_INT, ONLY: NEWIND=>PNEWIF
IMPLICIT REAL(KIND=DPSIZE) (A-Z)
REAL(KIND=DPSIZE) :: EVTREC
SAVE
INTEGER(KIND=ISIZE) :: ICALL,IDEF,IREV,NVNT,INDXS
DIMENSION :: IDEF(*),THETA(*),EVTREC(IREV,*),INDXS(*)
REAL(KIND=DPSIZE) :: G(GERD,*),HH(HERD,*)
INTEGER(KIND=ISIZE) :: FIRSTEM
FIRSTEM=IFIRSTEM
IF (ICALL <= 1) THEN
CALL ASSOCNMPRD4
! CALL ERROR ONLY ONCE
IDEF(2)=2
HH(1,1)=1.0D0
IDEF(3)=000
RETURN
ENDIF
IF (ICALL == 4) THEN
IF (NEWL2 == 1) THEN
CALL SIMEPS(EPS)
IF (IQUIT == 1) RETURN
ENDIF
ENDIF
! level 0
Y=F+EPS(001)
IF (FIRSTEM == 1) THEN !1
ENDIF !1
F=Y
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
SUBROUTINE PK(ICALL,IDEF,THETA,IREV,EVTREC,NVNT,INDXS,IRGG,GG,NETAS)
! PK SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA !
USED WITH ADVAN6 AND ADVAN7, AND TRANS1 ! CLEARANCE
PROPORTIONAL TO WEIGHT ! SCALING PARAMETER IS VOLUME/WEIGHT
SINCE DOSE IS WEIGHT-ADJUSTED
USE NMPRD4P
USE SIZES, ONLY: DPSIZE,ISIZE
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
USE NMPRD_REAL,ONLY: ETA,EPS
USE NMPRD_INT, ONLY:
MSEC=>ISECDER,MFIRST=>IFRSTDER,COMACT,COMSAV,IFIRSTEM
USE NMPRD_INT, ONLY: MDVRES,ETASXI,NPDE_MODE,NOFIRSTDERCODE
USE NMPRD_REAL, ONLY: DV_LOQ
USE NMPRD_INT, ONLY: IQUIT
USE PROCM_INT, ONLY: NEWIND=>PNEWIF
USE NMBAYES_REAL, ONLY: LDF
IMPLICIT REAL(KIND=DPSIZE) (A-Z)
REAL(KIND=DPSIZE) :: EVTREC
SAVE
INTEGER(KIND=ISIZE) :: FIRSTEM
INTEGER(KIND=ISIZE) :: ICALL,IDEF,IREV,NVNT,INDXS,IRGG,NETAS
DIMENSION ::
IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,GPKD+1,*)
FIRSTEM=IFIRSTEM
IF (ICALL <= 1) THEN
CALL ASSOCNMPRD4
! SET UP IDEF ARRAY:
IDEF( 1,0001)= -9
! CALL PK ONCE PER INDIV. REC.
IDEF( 1,0002)= 1
! ROW INDEX FOR SCALING PARAMETER FOR COMPT. 2
IDEF( 1,0003)= 0
IDEF( 1,0004)= 0
IDEF( 2,0003)= 0
IDEF( 2,0004)= 0
IDEF( 3,0002)= 3
CALL GETETA(ETA)
IF (IQUIT == 1) RETURN
RETURN
ENDIF
IF (NEWIND /= 2) THEN
IF (ICALL == 4) THEN
CALL SIMETA(ETA)
ELSE
CALL GETETA(ETA)
ENDIF
IF (IQUIT == 1) RETURN
ENDIF
! level 0
WT=EVTREC(NVNT,005)
KA=THETA(001)+ETA(001)
KE=THETA(002)+ETA(002)
CL=THETA(003)*WT+ETA(003)
S2=CL/KE/WT
P000001=KA
P000002=KE
! REGULAR CALL TO PK: ! WEIGHT
IF (FIRSTEM == 1) THEN
B000001=1.D0/KE/WT
! A000034 = DERIVATIVE OF S2 W.R.T. ETA(003)
A000034=B000001
B000002=-CL/KE/KE/WT
! A000035 = DERIVATIVE OF S2 W.R.T. ETA(002)
A000035=B000002
! A000046 = DERIVATIVE OF P000001 W.R.T. ETA(001)
A000046=1.D0
! A000047 = DERIVATIVE OF P000002 W.R.T. ETA(002)
A000047=1.D0
! ABSORPTION RATE CONSTANT
GG(0001,1,1)=P000001
GG(0001,0002,1)=A000046
! ELIMINATION RATE CONSTANT
GG(0002,1,1)=P000002
GG(0002,0003,1)=A000047
! SCALING
GG(0003,1,1)=S2
GG(0003,0003,1)=A000035
GG(0003,0004,1)=A000034
ELSE
GG(0001,1,1)=P000001
GG(0002,1,1)=P000002
GG(0003,1,1)=S2
ENDIF
IF (MSEC == 1) THEN
B000005=-1.D0/KE/KE/WT
B000006=-1.D0/KE/KE/WT
B000007=CL/KE/KE/KE/WT
B000008=CL/KE/KE/KE/WT
! A000041 = DERIVATIVE OF B000002 W.R.T. ETA(002)
A000041=B000008+B000007
! A000042 = DERIVATIVE OF A000035 W.R.T. ETA(002)
A000042=A000041
! A000043 = DERIVATIVE OF A000035 W.R.T. ETA(003)
A000043=B000006
GG(0003,0003,0003)=A000042
GG(0003,0004,0003)=A000043
ENDIF
RETURN
END
MODEL Routine To Be Used With ADVAN6
SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)
! DEFINES A 1 COMPARTMENT MODEL WITH DRUG DEPOT
COMPARTMENT ! COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT
USE PRMOD_CHAR, ONLY: NAME
USE SIZES, ONLY: DPSIZE,ISIZE,SD
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
INTEGER(KIND=ISIZE) :: IDNO,NCM,NPAR,IR,IATT,LINK,I,J
DIMENSION :: IATT(IR,*),LINK(IR,*)
SAVE
INTEGER(KIND=ISIZE), DIMENSION (2,7) :: MOD
CHARACTER(LEN=SD), DIMENSION(2) :: CMOD
DATA (MOD(I, 1),I= 1, 2)/&
! INITIAL STATUS: OFF ON
0,1 /
DATA (MOD(I, 2),I= 1, 2)/&
! ON/OFF ALLOWED: YES NO
1,0 /
DATA (MOD(I, 3),I= 1, 2)/&
! DOSE ALLOWED: YES YES
1,1 /
DATA (MOD(I, 4),I= 1, 2)/&
! DEFAULT FOR OBSERVATIONS: NO YES
0,1 /
DATA (MOD(I, 5),I= 1, 2)/&
! DEFAULT FOR DOSES: YES NO
1,0 /
DATA (MOD(I, 6),I= 1, 2)/&
0,0 /
DATA (MOD(I, 7),I= 1, 2)/&
0,0 /
DATA (CMOD(I),I= 1, 2) &
/’DEPOT’,’CENTRAL’/
FORALL (I=1:2) NAME(I)=CMOD(I)
FORALL (I=1:2,J=1:7) IATT(I,J)=MOD(I,J)
IDNO=9999
NCM= 2
NPAR=002
RETURN
END
DES Routine To Be Used With ADVAN6
SUBROUTINE DES (A,P,T,DADT,IR,DA,DP,DT)
! DES SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA
USE NMPRD4P
USE SIZES, ONLY: DPSIZE,ISIZE
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
USE NMPRD_INT, ONLY: IERPRD,NETEXT,IQUIT
USE NMPRD_CHAR,ONLY: ETEXT
USE NMPRD_INT, ONLY:
MSEC=>ISECDER,MFIRST=>IFRSTDER,IFIRSTEM,IFIRSTEMJAC
USE PRCOM_INT, ONLY: MITER
USE NMPRD_INT, ONLY: MDVRES,ETASXI,NPDE_MODE,NOFIRSTDERCODE
USE NMPRD_REAL, ONLY: DV_LOQ
USE PRMOD_INT, ONLY: ICALL=>ICALLD,IDEFD,IDEFA
IMPLICIT REAL(KIND=DPSIZE) (A-Z)
SAVE
INTEGER(KIND=ISIZE) :: IR
DIMENSION :: A(*),P(*),DADT(*),DA(IR,*),DP(IR,*),DT(*)
INTEGER(KIND=ISIZE) :: FIRSTEM,IFIRSTEMJACIN
IF(MITER==1.OR.MITER==4) IFIRSTEM=1
FIRSTEM=IFIRSTEM
IFIRSTEMJACIN=IFIRSTEMJAC
IF(NOFIRSTDERCODE/=1) THEN
IFIRSTEMJAC=FIRSTEM
ELSE
IFIRSTEMJAC=0
ENDIF
IF(IFIRSTEMJACIN==-2) RETURN
IF (ICALL == 1) THEN
CALL ASSOCNMPRD4
IDEFD(1)= 0
IDEFD(2)=0
DA( 1,1)=0014280
DA( 2,1)=0028441
DA( 3,1)=0028560
DA( 4,1)=0014311
DA( 5,1)=0028472
DA( 6,1)=0028592
DA( 7,1)=0000000
DP( 1,1)=0014280
DP( 2,1)=0028441
DP( 3,1)=0028560
DP( 4,1)=0000000
DT( 1)=0000000
RETURN
ENDIF
! level 0
! level 0
DADT(1)=-P(001)*A(1)
DADT(2)=P(001)*A(1)-P(002)*A(2)
IF (FIRSTEM == 1) THEN ! 1
! E000004 = DERIVATIVE OF DADT(1) W.R.T. A(001)
E000004=-P(001)
! F000081 = DERIVATIVE OF DADT(1) W.R.T. P(001)
F000081=-A(1)
! E000006 = DERIVATIVE OF DADT(2) W.R.T. A(001)
E000006=P(001)
! E000007 = DERIVATIVE OF DADT(2) W.R.T. A(002)
E000007=-P(002)
! F000082 = DERIVATIVE OF DADT(2) W.R.T. P(001)
F000082=A(1)
! F000083 = DERIVATIVE OF DADT(2) W.R.T. P(002)
F000083=-A(2)
ENDIF !1
IF (MSEC == 1) THEN
! E000005 = DERIVATIVE OF F000081 W.R.T. A(001)
E000005=-1.D0
! E000008 = DERIVATIVE OF F000082 W.R.T. A(001)
E000008=1.D0
! E000009 = DERIVATIVE OF F000083 W.R.T. A(002)
E000009=-1.D0
ENDIF !msec
IF (FIRSTEM == 1) THEN !2
DA( 1,1)=E000004
DA( 2,1)=E000006
DA( 3,1)=E000007
DP( 1,1)=F000081
DP( 2,1)=F000082
DP( 3,1)=F000083
ENDIF !2
IF (MSEC == 1) THEN
DA( 4,1)=E000005
DA( 5,1)=E000008
DA( 6,1)=E000009
ENDIF
RETURN
END
TOL Routine To Be Used With ADVAN6
! TOL SUBROUTINE FOR THE THEOPHYLLINE POPULATION DATA SUBROUTINE TOL(NRD,ANRD,NRDC,ANRDC)
USE SIZES, ONLY: ISIZE
INTEGER(KIND=ISIZE) :: NRD(0:*), ANRD(0:*), NRDC(0:*), ANRDC(0:*)
NRD(1)=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)
! DEFINES A 1 COMPARTMENT LINEAR MODEL WITH FIRST-ORDER
ABSORPTION ! COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT
USE PRMOD_CHAR, ONLY: NAME
USE SIZES, ONLY: DPSIZE,ISIZE,SD
USE PRDIMS, ONLY: GPRD,HPRD,GERD,HERD,GPKD
INTEGER(KIND=ISIZE) :: IDNO,NCM,NPAR,IR,IATT,LINK,I,J
DIMENSION :: IATT(IR,*),LINK(IR,*)
SAVE
INTEGER(KIND=ISIZE), DIMENSION (2,7) :: MOD
CHARACTER(LEN=SD), DIMENSION(2) :: CMOD
DATA (MOD(I, 1),I= 1, 2)/&
! INITIAL STATUS: OFF ON
0,1 /
DATA (MOD(I, 2),I= 1, 2)/&
! ON/OFF ALLOWED: YES NO
1,0 /
DATA (MOD(I, 3),I= 1, 2)/&
! DOSE ALLOWED: YES YES
1,1 /
DATA (MOD(I, 4),I= 1, 2)/&
! DEFAULT FOR OBSERVATIONS: NO YES
0,1 /
DATA (MOD(I, 5),I= 1, 2)/&
! DEFAULT FOR DOSES: YES NO
1,0 /
DATA (MOD(I, 6),I= 1, 2)/&
0,0 /
DATA (MOD(I, 7),I= 1, 2)/&
0,0 /
DATA (CMOD(I),I= 1, 2) &
! COMPARTMENT NAMES
/’DEPOT’,’CENTRAL’/
FORALL (I=1:2) NAME(I)=CMOD(I)
FORALL (I=1:2,J=1:7) IATT(I,J)=MOD(I,J)
IDNO=9999
NCM= 2
NPAR=002
! SET LINK: ! K12
LINK( 1,002)=001
! K20
LINK( 2,003)=002
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 ...