C PK SUBROUTINE FOR THE PHENOBARB POPULATION DATA
C TYPICAL VALUES RETURNED
C USED WITH ADVAN1 AND TRANS2
C CLEARANCE AND VOLUME PROPORTIONAL TO WEIGHT
C PROPORTIONALITY CONSTANT FOR VOLUME DEPENDS ON APGAR
C
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 TVCL,TVVD
IF (ICALL.GT.1) GO TO 1000
C SET UP IDEF ARRAY:
IDEF(1,1)=-9
C ROW INDEX OF SCALING PARAMETER
IDEF(3,1)=3
C CALL PK ONCE PER INDIV. REC.
IDEF(1,2)=1
RETURN
1000 CONTINUE
C REGULAR CALLS TO PK:
C WEIGHT
WT=EVTREC(1,4)
C APGAR
APGR=EVTREC(1,5)
C CLEARANCE
TVCL=THETA(1)*WT
GG(1,1)=TVCL
GG(1,2)=TVCL
C VOLUME
TVVD=THETA(2)*WT
IF (APGR.LE.2) TVVD=THETA(3)*TVVD
GG(2,1)=TVVD
GG(2,3)=TVVD
C SCALING
GG(3,1)=TVVD
GG(3,3)=TVVD
RETURN
END
C PK SUBROUTINE FOR THE PHENOBARB POPULATION DATA
C ILLUSTRATING DATA SIMULATION
C USED WITH ADVAN1 AND TRANS2
C CLEARANCE AND VOLUME PROPORTIONAL TO WEIGHT
C PROPORTIONALITY CONSTANT FOR VOLUME DEPENDS ON APGAR
C
SUBROUTINE PK (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,IRGG,GG,NETAS)
DIMENSION IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,*)
DIMENSION ETA(2)
DOUBLE PRECISION THETA,GG,ETA
DOUBLE PRECISION TVCL,TVVD,CL,VD
IF (ICALL.GT.1) GO TO 1000
C SET UP IDEF ARRAY:
IDEF(1,1)=-9
C ROW INDEX OF SCALING PARAMETER
IDEF(3,1)=3
C CALL PK ONCE PER INDIV. REC.
IDEF(1,2)=1
RETURN
1000 CONTINUE
C REGULAR CALLS TO PK:
C WEIGHT
WT=EVTREC(1,4)
C APGAR
APGR=EVTREC(1,5)
IF (ICALL.EQ.4) GO TO 2000
C DATA ANALYTIC CALL:
C CLEARANCE
TVCL=THETA(1)*WT
GG(1,1)=TVCL
GG(1,2)=TVCL
C VOLUME
TVVD=THETA(2)*WT
IF (APGR.LE.2) TVVD=THETA(3)*TVVD
GG(2,1)=TVVD
GG(2,3)=TVVD
C SCALING
GG(3,1)=TVVD
GG(3,3)=TVVD
RETURN
2000 CONTINUE
C SIMULATION CALL:
CALL SIMETA (ETA)
C CLEARANCE
CL=THETA(1)*WT*EXP(ETA(1))
GG(1,1)=CL
C VOLUME
EVTREC(1,6)=1
VD=THETA(2)*WT*EXP(ETA(2))
IF (APGR.LE.2) THEN
EVTREC(1,6)=2
VD=THETA(3)*VD
ENDIF
GG(2,1)=VD
C SCALING
GG(3,1)=VD
RETURN
END
C PK SUBROUTINE FOR THE PHENOBARB POPULATION DATA
C SUBJECT-SPECIFIC VALUES RETURNED
C USED WITH ADVAN1 AND TRANS2
C CLEARANCE AND VOLUME PROPORTIONAL TO WEIGHT
C PROPORTIONALITY CONSTANT FOR VOLUME DEPENDS ON APGAR
C
SUBROUTINE PK (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,IRGG,GG,NETAS)
DIMENSION IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,*)
DIMENSION ETA(2)
DOUBLE PRECISION THETA,GG,ETA
DOUBLE PRECISION CL,VD
IF (ICALL.GT.1) GO TO 1000
C SET UP IDEF ARRAY:
IDEF(1,1)=-9
C ROW INDEX OF SCALING PARAMETER
IDEF(3,1)=3
C CALL PK ONCE PER INDIV. REC.
IDEF(1,2)=1
C INITIALIZE GETETA
CALL GETETA (ETA)
RETURN
1000 CONTINUE
C REGULAR CALLS TO PK:
C WEIGHT
WT=EVTREC(1,4)
C APGAR
APGR=EVTREC(1,5)
C GETETA
CALL GETETA (ETA)
C CLEARANCE
CL=THETA(1)*WT*EXP(ETA(1))
GG(1,1)=CL
GG(1,2)=CL
C VOLUME
VD=THETA(2)*WT*EXP(ETA(2))
IF (APGR.LE.2) VD=THETA(3)*VD
GG(2,1)=VD
GG(2,3)=VD
C SCALING
GG(3,1)=VD
GG(3,3)=VD
RETURN
END
See figure in file fig4.pdf
C PK SUBROUTINE FOR THE PHENOBARB POPULATION DATA
C SUBJECT-SPECIFIC VALUES RETURNED MIXTURE MODEL
C USED WITH ADVAN1 AND TRANS2
C
SUBROUTINE PK (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,IRGG,GG,NETAS)
DIMENSION IDEF(7,*),THETA(*),EVTREC(IREV,*),INDXS(*),GG(IRGG,*)
COMMON /ROCM11/ MIXNUM,MIXEST
COMMON /NMPRD4/ EST
DIMENSION ETA(4)
DOUBLE PRECISION THETA,GG,ETA
DOUBLE PRECISION CL,VD,EST
IF (ICALL.GT.1) GO TO 1000
C SET UP IDEF ARRAY:
IDEF(1,1)=-9
C ROW INDEX OF SCALING PARAMETER
IDEF(3,1)=3
C CALL PK ONCE PER INDIV. REC.
IDEF(1,2)=1
C INITIALIZE GETETA
CALL GETETA (ETA)
RETURN
1000 CONTINUE
C REGULAR CALLS TO PK:
C GETETA
CALL GETETA (ETA)
C MIXTURE MIXNUM ESTIMATE
EST=MIXEST
C CLEARANCE
IF (MIXNUM.EQ.1) THEN
CL=THETA(1)*EXP(ETA(1))
GG(1,1)=CL
GG(1,2)=CL
ELSE
CL=THETA(2)*THETA(1)*EXP(ETA(3))
GG(1,1)=CL
GG(1,4)=CL
ENDIF
C VOLUME
IF (MIXNUM.EQ.1) THEN
VD=THETA(3)*EXP(ETA(2))
GG(2,1)=VD
GG(2,3)=VD
ELSE
VD=THETA(4)*THETA(3)*EXP(ETA(4))
GG(2,1)=VD
GG(2,5)=VD
ENDIF
C SCALING
GG(3,1)=VD
IF (MIXNUM.EQ.1) THEN
GG(3,3)=VD
ELSE
GG(3,5)=VD
ENDIF
RETURN
END
SUBROUTINE MIX (ICALL,NSPOP,P)
COMMON /ROCM0/ THETA(20)
DIMENSION P(*)
DOUBLE PRECISION P,THETA
P(1)=THETA(5)
P(2)=1.-THETA(5)
NSPOP=2
RETURN
END
C PK SUBROUTINE FOR SINGLE-SUBJECT DATA
C USED WITH ADVAN2 AND TRANS1
C
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
IF (ICALL.GT.1) GO TO 1000
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
RETURN
1000 CONTINUE
C REGULAR CALL TO PK:
C ELIMINATION RATE CONSTANT
GG(1,1)=THETA(2)
C ABSORPTION RATE CONSTANT
GG(3,1)=THETA(1)
C SCALING
GG(4,1)=THETA(3)
RETURN
END
C PK ROUTINE FOR SINGLE-SUBJECT PHARMACODYNAMIC DATA
C USED WITH ADVAN7 AND TRANS1
C
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 K12,K20,K23,K30,VD,VE
IF (ICALL.GT.1) GO TO 1000
C SET UP IDEF ARRAY:
IDEF(1,1)=-9
C ROW INDEX OF SCALING PARAMETER
IDEF(3,3)=5
C CALL PK ONCE PER INDIV. REC.
IDEF(1,2)=1
RETURN
1000 CONTINUE
C REGULAR CALLS TO PK:
C K12
K12=1.94
GG(1,1)=K12
C K20
K20=.102
GG(2,1)=K20
C K23
K23=.001*K20
GG(3,1)=K23
C K30 (KEO)
K30=THETA(1)
GG(4,1)=K30
C SCALING
VD=32
VE=VD*K23/K30
GG(5,1)=VE
RETURN
END
C ERROR SUBROUTINE FOR THE PHENOBARB POPULATION DATA
C EXPONENTIAL ERROR MODEL
C
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
HH(1)=F
RETURN
END
C ERROR ROUTINE FOR THE PHENOBARB POPULATION DATA
C ILLUSTRATING DATA SIMULATION
C EXPONENTIAL ERROR MODEL
C
SUBROUTINE ERROR (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,F,G,HH)
DIMENSION IDEF(*),THETA(*),EVTREC(IREV,*),INDXS(*),G(*),HH(*)
DIMENSION EPS(1)
DOUBLE PRECISION THETA,F,G,HH,EPS
IF (ICALL.EQ.2) HH(1)=F
IF (ICALL.EQ.4) THEN
CALL SIMEPS (EPS)
F=F*EXP(EPS(1))
ENDIF
RETURN
END
C ERROR ROUTINE FOR SINGLE-SUBJECT DATA
C ADDITIVE ERROR MODEL
C
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
C ERROR ROUTINE FOR SINGLE-SUBJECT DATA
C ILLUSTRATING DATA SIMULATION
C ADDITIVE ERROR MODEL
C
SUBROUTINE ERROR (ICALL,IDEF,THETA,IREV,EVTREC,N,INDXS,F,G,HH)
DIMENSION IDEF(*),THETA(*),EVTREC(IREV,*),INDXS(*),G(*),HH(*)
DIMENSION ETA(1)
DOUBLE PRECISION THETA,F,G,HH,ETA
IF (ICALL.EQ.4) THEN
CALL SIMETA (ETA)
F=F+ETA(1)
RETURN
ENDIF
C CALL ERROR ONLY ONCE FOR DATA ANALYSIS
IDEF(2)=2
HH(1)=1.
RETURN
END
C ERROR ROUTINE FOR SINGLE-SUBJECT PHARMACODYNAMIC DATA
C CONSTANT CV ERROR MODEL
C
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
DOUBLE PRECISION EMAX,C50,E
IF (ICALL.EQ.1) RETURN
C EMAX
EMAX=THETA(2)
C C50
C50=THETA(3)
C EFFECT
E=EMAX*F/(F+C50)
F=E
C CONSTANT CV ERROR MODEL
HH(1)=F
RETURN
END
C ERROR ROUTINE FOR SINGLE-SUBJECT PHARMACODYNAMIC DATA
C ILLUSTRATING ERROR-DEFINED ITEMS
C CONSTANT CV ERROR MODEL
C
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
DOUBLE PRECISION EMAX,C50,E,CE,A,CP
COMMON /NMPRD4/ CP,CE
COMMON /PROCM4/ A(3)
IF (ICALL.EQ.1) RETURN
C CP AND CE
CP=A(2)/32.
CE=F
C EMAX
EMAX=THETA(2)
C C50
C50=THETA(3)
C EFFECT
E=EMAX*F/(F+C50)
F=E
C CONSTANT CV ERROR MODEL
HH(1)=F
RETURN
END
1 0. 25.0 1.4 7 1 1
1 2.0 1.4 7 17.3 0 0
1 12.5 3.5 1.4 7 1 1
1 24.5 3.5 1.4 7 1 1
1 37.0 3.5 1.4 7 1 1
1 48.0 3.5 1.4 7 1 1
1 60.5 3.5 1.4 7 1 1
1 72.5 3.5 1.4 7 1 1
1 85.3 3.5 1.4 7 1 1
1 96.5 3.5 1.4 7 1 1
1 108.5 3.5 1.4 7 1 1
1 112.5 1.4 7 31.0 0 0
2 0. 15.0 1.5 9 1 1
2 2.0 1.5 9 9.7 0 0
2 4.0 3.8 1.5 9 1 1
2 16.0 3.8 1.5 9 1 1
2 27.8 3.8 1.5 9 1 1
2 40.0 3.8 1.5 9 1 1
2 52.0 3.8 1.5 9 1 1
2 63.5 1.5 9 24.6 0 0
2 64.0 3.8 1.5 9 1 1
2 76.0 3.8 1.5 9 1 1
2 88.0 3.8 1.5 9 1 1
2 100.0 3.8 1.5 9 1 1
2 112.0 3.8 1.5 9 1 1
2 124.0 3.8 1.5 9 1 1
2 135.5 1.5 9 33.0 0 0
3 0. 30.0 1.5 6 1 1
3 1.5 1.5 6 18.0 0 0
3 11.5 3.7 1.5 6 1 1
3 23.5 3.7 1.5 6 1 1
3 35.5 3.7 1.5 6 1 1
3 47.5 3.7 1.5 6 1 1
3 59.3 3.7 1.5 6 1 1
3 73.0 3.7 1.5 6 1 1
3 83.5 1.5 6 23.8 0 0
3 84.0 3.7 1.5 6 1 1
3 96.5 3.7 1.5 6 1 1
3 108.5 3.7 1.5 6 1 1
3 120.0 3.7 1.5 6 1 1
3 132.0 3.7 1.5 6 1 1
3 134.3 1.5 6 24.3 0 0
FILE FILESTREAM PROB PHENOBARB POPULATION DATA DATA 1 0 0 8 ITEM 1 6 8 11 1 INDX 7 2 3 LABL ID TIME AMT WT APGR CP EVID MDV FORM (7F7.0,1X,F1.0) STRC 3 2 1 1 0 1 THCN 1 THTA .0047 .99 1.0 LOWR 0 0 0 UPPR +1000000+1000000+1000000 DIAG .05 .03 DIAG .02 ESTM 0 500 3 5 COVR 0 TABL 0 1 TABL 5 1 0 2 0 3 0 4 0 5 0 SCAT 0 7 SCAT 9 6 0 0 0 1 SCAT 9 10 SCAT 4 10 SCAT 5 10 SCAT 9 11 SCAT 4 11 SCAT 5 11
$PROB PHENOBARB POPULATION DATA
$DATA DATA1 (6F7.0)
$INPUT ID TIME AMT WT APGR CP=DV
$SUBROUTINES ADVAN1 TRANS2
$PK
;CLEARANCE AND VOLUME PROPORTIONAL TO WEIGHT
;PROPORTIONALITY CONSTANT FOR VOLUME DEPENDS ON APGAR
CALLFL=1
CL=THETA(1)*WT*EXP(ETA(1))
TVVD=THETA(2)*WT
IF (APGR.LE.2) TVVD=THETA(3)*TVVD
V=TVVD*EXP(ETA(2))
S1=V
$ERROR
Y=F*EXP(EPS(1))
$THETA (0,.0047) (0,.99) (0,1.0)
$OMEGA .05 .03
$SIGMA .02
$ESTIM MAXEVAL=500 PRINT=5
$COVAR
$TABLE ID TIME AMT WT APGR
$SCAT CP VS PRED UNIT
$SCAT RES VS PRED
$SCAT RES VS WT
$SCAT RES VS APGR
$SCAT WRES VS PRED
$SCAT WRES VS WT
$SCAT WRES VS APGR
NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) DOUBLE PRECISION NONMEM VERSION IV LEVEL 1.0
DEVELOPED AND PROGRAMMED BY STUART BEAL AND LEWIS SHEINER
PROBLEM NO. 1
PHENOBARB POPULATION DATA
DATA CHECKOUT RUN: NO
DATA SET LOCATED ON UNIT NO.: 2
THIS UNIT TO BE REWOUND: NO
NO. OF DATA ITEMS IN DATA SET: 8
ID DATA ITEM IS DATA ITEM NO.: 1
DEP VARIABLE IS DATA ITEM NO.: 6
MDV DATA ITEM IS DATA ITEM NO.: 8
INDICES PASSED TO SUBROUTINE PRED ARE:
7 2 3 0 0 0 0 0 0
0 0
LABELS FOR DATA ITEMS ARE:
ID TIME AMT WT APGR CP EVID MDV
FORMAT FOR DATA IS:
(7F7.0,1X,F1.0)
TOT. NO. OF DATA RECS: 744
TOT. NO. OF OBS RECS: 155
TOT. NO. OF INDIVIDUALS: 59
LENGTH OF THETA: 3
OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 2
SIGMA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1
INITIAL ESTIMATE OF THETA:
LOWER BOUND INITIAL EST UPPER BOUND
0.0000E+00 0.4700E-02 0.1000E+07
0.0000E+00 0.9900E+00 0.1000E+07
0.0000E+00 0.1000E+01 0.1000E+07
INITIAL ESTIMATE OF OMEGA:
0.5000E-01
0.0000E+00 0.3000E-01
INITIAL ESTIMATE OF SIGMA:
0.2000E-01
ESTIMATION STEP OMITTED: NO
NO. OF FUNCT. EVALS. ALLOWED: 500
NO. OF SIG. FIGURES REQUIRED: 3
INTERMEDIATE PRINTOUT: YES
MSF OUTPUT: NO
COVARIANCE STEP OMITTED: NO
EIGENVLS. PRINTED: NO
SPECIAL COMPUTATION: NO
TABLES STEP OMITTED: NO
NO. OF TABLES: 1
TABLES PRINTED: YES
USER-CHOSEN DATA ITEMS FOR TABLE 1,
IN THE ORDER THEY WILL APPEAR IN THE TABLE, ARE:
ID TIME AMT WT APGR
SCATTERPLOT STEP OMITTED: NO
NO. OF PAIRS OF ITEMS GENERATING
FAMILIES OF SCATTERPLOTS: 7
ITEMS TO BE SCATTERED ARE: PRED CP
UNIT SLOPE LINE INCLUDED
ITEMS TO BE SCATTERED ARE: PRED RES
ITEMS TO BE SCATTERED ARE: WT RES
ITEMS TO BE SCATTERED ARE: APGR RES
ITEMS TO BE SCATTERED ARE: PRED WRES
ITEMS TO BE SCATTERED ARE: WT WRES
ITEMS TO BE SCATTERED ARE: APGR WRES
DOUBLE PRECISION PREDPP VERSION III LEVEL 1.0
ONE COMPARTMENT MODEL (ADVAN1)
MAXIMUM NO. OF BASIC PK PARAMETERS: 2
BASIC PK PARAMETERS (AFTER TRANSLATION):
ELIMINATION RATE (K) IS BASIC PK PARAMETER NO.: 1
TRANSLATOR WILL CONVERT PARAMETERS CLEARANCE (CL) AND VOLUME (V) TO K (TRANS2)
COMPARTMENT ATTRIBUTES
COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT
STATUS ALLOWED ALLOWED FOR DOSE FOR OBS.
1 CENTRAL ON NO YES YES YES
2 OUTPUT OFF YES NO NO NO
ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG COMPT. NO. INDICES SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB FRACTION RATE DURATION LAG 1 3 * * * * 2 * - - - - - PARAMETER IS NOT ALLOWED FOR THIS MODEL * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; WILL DEFAULT TO ONE IF APPLICABLE
DATA ITEM INDICES USED BY PRED ARE: EVENT ID DATA ITEM IS DATA ITEM NO.: 7 TIME DATA ITEM IS DATA ITEM NO.: 2 DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 3
PK SUBROUTINE CALLED ONCE PER INDIVIDUAL RECORD. PK SUBROUTINE NOT CALLED AT ADDITIONAL DOSE OR LAGGED DOSE TIMES.
ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD.
FILE FILESTREAM PROB PHENOBARB POPULATION DATA DATA 1 0 0 8 ITEM 1 6 8 11 1 INDX 7 2 3 LABL ID TIME AMT WT APGR CP EVID MDV FORM (7F7.0,1X,F1.0) STRC 3 2 1 1 0 1 THCN 1 THTA .0047 .99 1.0 LOWR 0 0 0 UPPR +1000000+1000000+1000000 DIAG .05 .03 DIAG .02 ESTM 0 500 3 5 1 COVR 0 TABL 0 1 TABL 7 1 0 2 0 3 0 4 0 5 0 12 0 13 0 SCAT 0 7 SCAT 9 6 0 0 0 1 SCAT 9 10 SCAT 9 11 SCAT 4 12 SCAT 5 12 SCAT 4 13 SCAT 5 13
$PROB PHENOBARB POPULATION DATA
$DATA DATA2 (6F7.0)
$INPUT ID TIME AMT WT APGR CP=DV
$SUBROUTINES ADVAN1 TRANS2
$PK
;CLEARANCE AND VOLUME PROPORTIONAL TO WEIGHT
;PROPORTIONALITY CONSTANT FOR VOLUME DEPENDS ON APGAR
CALLFL=1
CL=THETA(1)*WT*EXP(ETA(1))
TVVD=THETA(2)*WT
IF (APGR.LE.2) TVVD=THETA(3)*TVVD
V=TVVD*EXP(ETA(2))
S1=V
$ERROR
Y=F*EXP(EPS(1))
$THETA (0,.0047) (0,.99) (0,1.0)
$OMEGA .05 .03
$SIGMA .02
$ESTIM MAXEVAL=500 PRINT=5 POSTHOC
$COVAR
$TABLE ID TIME AMT WT APGR ETA1 ETA2
$SCAT CP VS PRED UNIT
$SCAT RES VS PRED
$SCAT WRES VS PRED
$SCAT ETA1 VS WT
$SCAT ETA1 VS APGR
$SCAT ETA2 VS WT
$SCAT ETA2 VS APGR
FILE FILESTREAM PROB PHENOBARB POPULATION DATA MIXTURE MODEL DATA 1 0 0 8 ITEM 1 6 8 11 1 1 INDX 7 2 3 LABL ID TIME AMT WT APGR CP EVID MDV EST FORM (7F7.0,1X,F1.0) STRC 5 4 1 0 1 1 STRC 2 2 THCN 1 THTA .0047 1.0 .99 1.0 .5 LOWR 0 0 0 0 0 UPPR +1000000+1000000+1000000+1000000 1.0 BLST .05 .01 .03 DIAG .02 ESTM 0 500 3 5 SCAT 0 8 SCAT 9 6 0 0 0 1 SCAT 9 10 SCAT 4 10 SCAT 5 10 SCAT 9 11 SCAT 4 11 SCAT 5 11 SCAT 4 12
$PROB PHENOBARB POPULATION DATA MIXTURE MODEL
$DATA DATA2 (6F7.0)
$INPUT ID TIME AMT WT APGR CP=DV
$SUBROUTINES ADVAN1 TRANS2 MIX=mix
$PK
CALLFL=1
EST=MIXEST
CL1=THETA(1)*EXP(ETA(1))
V1=THETA(3)*EXP(ETA(2))
CL2=THETA(2)*THETA(1)*EXP(ETA(3))
V2=THETA(4)*THETA(3)*EXP(ETA(4))
Q=1
IF (MIXNUM.EQ.2) Q=0
CL=Q*CL1+(1-Q)*CL2
V=Q*V1+(1-Q)*V2
S1=V
$ERROR
Y=F*EXP(EPS(1))
$THETA (0,.0047) (0,1) (0,.99) (0,1) (0,.5,1)
$OMEGA BLOCK(2) .05 .01 .03
$OMEGA BLOCK(2) SAME
$SIGMA .02
$ESTM MAXEVAL=500 PRINT=5
$SCAT CP VS PRED UNIT
$SCAT RES VS PRED
$SCAT RES VS WT
$SCAT RES VS APGR
$SCAT WRES VS PRED
$SCAT WRES VS WT
$SCAT WRES VS APGR
$SCAT EST VS WT
See figure in file fig24.pdf
FILE NULL
PROB THEOPHYLLINE SINGLE SUBJECT DATA
DATA 0 0 11 6
ITEM 6 3 5 11 1
INDX 4 2 1
LABL DOSE TIME CP EVID MDV ID
FORM
(4F7.0,1X,F1.0,1X,F2.0)
320 .0 1 1 1
.27 1.71 0 0 1
.52 7.91 0 0 2
1. 8.31 0 0 3
1.92 8.33 0 0 4
3.5 6.85 0 0 5
5.02 6.08 0 0 6
7.03 5.4 0 0 7
9. 4.55 0 0 8
12. 3.01 0 0 9
24.3 .90 0 0 10
STRC 3 1 0 1
THCN 1
THTA 1.7 .102 29.
LOWR 0. 0. 0.
UPPR +1000000+1000000+1000000
DIAG 2
ESTM 0 240 3 2
COVR 0 0 0 0 1
TABL 0 1
TABL 1 2
SCAT 0 4
SCAT 2 3
SCAT 2 7
SCAT 2 8
SCAT 3 7 0 0 0 1
$PROBLEM THEOPHYLLINE SINGLE SUBJECT DATA $INPUT DOSE=AMT TIME CP=DV $DATA DATA3 (3F7.0) $SUBROUTINES ADVAN2 $PK CALLFL=1 KA=THETA(1) K=THETA(2) SC=THETA(3) $ERROR Y=F+ERR(1) $THETA (0,1.7) (0,.102) (0,29) $ESTIMATION MAXEVAL=240 PRINT=2 $COVR $TABLE TIME $SCAT CP VS TIME $SCAT PRED VS TIME $SCAT RES VS TIME $SCAT PRED VS CP UNIT
NONLINEAR MIXED EFFECTS MODEL PROGRAM (NONMEM) DOUBLE PRECISION NONMEM VERSION IV LEVEL 1.0
DEVELOPED AND PROGRAMMED BY STUART BEAL AND LEWIS SHEINER
PROBLEM NO. 1
THEOPHYLLINE SINGLE SUBJECT DATA
DATA CHECKOUT RUN: NO
NO. OF DATA RECS IN DATA SET: 11
NO. OF DATA ITEMS IN DATA SET: 6
ID DATA ITEM IS DATA ITEM NO.: 6
DEP VARIABLE IS DATA ITEM NO.: 3
MDV DATA ITEM IS DATA ITEM NO.: 5
INDICES PASSED TO SUBROUTINE PRED ARE:
4 2 1 0 0 0 0 0 0
0 0
LABELS FOR DATA ITEMS ARE:
DOSE TIME CP EVID MDV ID
FORMAT FOR DATA IS:
(4F7.0,1X,F1.0,1X,F2.0)
TOT. NO. OF OBS RECS: 10
TOT. NO. OF INDIVIDUALS: 10
LENGTH OF THETA: 3
OMEGA HAS SIMPLE DIAGONAL FORM WITH DIMENSION: 1
INITIAL ESTIMATE OF THETA:
LOWER BOUND INITIAL EST UPPER BOUND
0.0000E+00 0.1700E+01 0.1000E+07
0.0000E+00 0.1020E+00 0.1000E+07
0.0000E+00 0.2900E+02 0.1000E+07
ESTIMATION STEP OMITTED: NO
NO. OF FUNCT. EVALS. ALLOWED: 240
NO. OF SIG. FIGURES REQUIRED: 3
INTERMEDIATE PRINTOUT: YES
MSF OUTPUT: NO
COVARIANCE STEP OMITTED: NO
EIGENVLS. PRINTED: NO
SPECIAL COMPUTATION: YES
TABLES STEP OMITTED: NO
NO. OF TABLES: 1
TABLES PRINTED: YES
USER-CHOSEN DATA ITEMS FOR TABLE 1,
IN THE ORDER THEY WILL APPEAR IN THE TABLE, ARE:
TIME
SCATTERPLOT STEP OMITTED: NO
NO. OF PAIRS OF ITEMS GENERATING
FAMILIES OF SCATTERPLOTS: 4
ITEMS TO BE SCATTERED ARE: TIME CP
ITEMS TO BE SCATTERED ARE: TIME PRED
ITEMS TO BE SCATTERED ARE: TIME RES
ITEMS TO BE SCATTERED ARE: CP PRED
UNIT SLOPE LINE INCLUDED
DOUBLE PRECISION PREDPP VERSION III LEVEL 1.0
ONE COMPARTMENT MODEL WITH FIRST-ORDER ABSORPTION (ADVAN2)
MAXIMUM NO. OF BASIC PK PARAMETERS: 3
BASIC PK PARAMETERS (AFTER TRANSLATION):
ELIMINATION RATE (K) IS BASIC PK PARAMETER NO.: 1
ABSORPTION RATE (KA) IS BASIC PK PARAMETER NO.: 3
COMPARTMENT ATTRIBUTES
COMPT. NO. FUNCTION INITIAL ON/OFF DOSE DEFAULT DEFAULT
STATUS ALLOWED ALLOWED FOR DOSE FOR OBS.
1 DEPOT OFF YES YES YES NO
2 CENTRAL ON NO YES NO YES
3 OUTPUT OFF YES NO NO NO
ADDITIONAL PK PARAMETERS - ASSIGNMENT OF ROWS IN GG COMPT. NO. INDICES SCALE BIOAVAIL. ZERO-ORDER ZERO-ORDER ABSORB FRACTION RATE DURATION LAG 1 * * * * * 2 4 * * * * 3 * - - - - - PARAMETER IS NOT ALLOWED FOR THIS MODEL * PARAMETER IS NOT SUPPLIED BY PK SUBROUTINE; WILL DEFAULT TO ONE IF APPLICABLE
DATA ITEM INDICES USED BY PRED ARE: EVENT ID DATA ITEM IS DATA ITEM NO.: 4 TIME DATA ITEM IS DATA ITEM NO.: 2 DOSE AMOUNT DATA ITEM IS DATA ITEM NO.: 1
PK SUBROUTINE CALLED ONCE PER INDIVIDUAL RECORD. PK SUBROUTINE NOT CALLED AT ADDITIONAL DOSE OR LAGGED DOSE TIMES.
DURING SIMULATION, ERROR SUBROUTINE CALLED WITH EVERY EVENT RECORD. OTHERWISE, ERROR SUBROUTINE CALLED ONCE IN THIS PROBLEM.
FILE NULL
PROB THEOPHYLLINE SINGLE SUBJECT DATA PHARMACODYNAMICS
DATA 0 0 11 6
ITEM 6 3 5 11 1
INDX 4 2 1
LABL DOSE TIME EFF EVID MDV ID
FORM
(4F7.0,1X,F1.0,1X,F2.0)
320 .0 1 1 1
.27 .094 0 0 1
.52 .163 0 0 2
1. .317 0 0 3
1.92 .544 0 0 4
3.5 .689 0 0 5
5.02 .473 0 0 6
7.03 .733 0 0 7
9. .667 0 0 8
12. .327 0 0 9
24.3 .151 0 0 10
STRC 3 1 0 1
THCN 1
THTA 1. 1. 5.
LOWR 0. 0. 0.
UPPR +1000000+1000000+1000000
DIAG 2
ESTM 0 240 3 2
COVR 0 0 0 0 1
TABL 0 1
TABL 1 2
SCAT 0 4
SCAT 2 3
SCAT 2 7
SCAT 2 8
SCAT 3 7 0 0 0 1
$PROBLEM THEOPHYLLINE SINGLE SUBJECT DATA PHARMACODYNAMICS $INPUT DOSE=AMT TIME EFF=DV $DATA DATA4 (3F7.0) $SUBROUTINES ADVAN7 $MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL) COMP=(EFFECT,DEFOBS) $PK CALLFL=1 K12=1.94 K20=.102 K23=.001*K20 K30=THETA(1) VD=32 S3=VD*K23/K30 $ERROR EMAX=THETA(2) C50=THETA(3) E=EMAX*F/(F+C50) Y=E*(1+ETA(1)) $THETA (0,1) (0,1) (0,5) $ESTIMATION MAXEVALS=240 PRINT=2 $COVR $TABLE TIME $SCAT EFF VS TIME $SCAT PRED VS TIME $SCAT RES VS TIME $SCAT PRED VS EFF UNIT
FILE NULL
PROB THEOPHYLLINE SINGLE SUBJECT DATA PHARMACODYNAMICS
DATA 0 0 11 6
ITEM 6 3 5 11 1 0 0 0 0 0 2
INDX 4 2 1
LABL DOSE TIME EFF EVID MDV ID CP CE
FORM
(4F7.0,1X,F1.0,1X,F2.0)
320 .0 1 1 1
.27 .094 0 0 1
.52 .163 0 0 2
1. .317 0 0 3
1.92 .544 0 0 4
3.5 .689 0 0 5
5.02 .473 0 0 6
7.03 .733 0 0 7
9. .667 0 0 8
12. .327 0 0 9
24.3 .151 0 0 10
STRC 3 1 0 1
THCN 1
THTA 1. 1. 5.
LOWR 0. 0. 0.
UPPR +1000000+1000000+1000000
DIAG 2
ESTM 0 240 3 2
COVR 0 0 0 0 1
TABL 0 1
TABL 3 2 0 10 0 11 0
SCAT 0 8
SCAT 2 3
SCAT 2 7
SCAT 2 8
SCAT 3 7 0 0 0 1
SCAT 11 7
SCAT 10 11
SCAT 2 10
SCAT 2 11
$PROBLEM THEOPHYLLINE SINGLE SUBJECT DATA PHARMACODYNAMICS $INPUT DOSE=AMT TIME EFF=DV $DATA DATA4 (3F7.0) $SUBROUTINES ADVAN7 $MODEL COMP=(DEPOT,DEFDOSE) COMP=(CENTRAL) COMP=(EFFECT,DEFOBS) $PK CALLFL=1 K12=1.94 K20=.102 K23=.001*K20 K30=THETA(1) VD=32 S3=VD*K23/K30 $ERROR CP=A(2)/VD CE=F EMAX=THETA(2) C50=THETA(3) E=EMAX*F/(F+C50) Y=E*(1+ETA(1)) $THETA (0,1) (0,1) (0,5) $ESTIMATION MAXEVALS=240 PRINT=2 $COVR $TABLE TIME CP CE $SCAT EFF VS TIME $SCAT PRED VS TIME $SCAT RES VS TIME $SCAT PRED VS EFF UNIT $SCAT PRED VS CE $SCAT CE VS CP $SCAT CP VS TIME $SCAT CE VS TIME
See figure in file fig33.pdf
See figure in file fig34.pdf
See figure in file fig35.pdf
See figure in file fig36.pdf
C INFN ROUTINE FOR COMPUTING LINEARLY INTERPOLATED VALUES
C OF AN INDEPENDENT VARIABLE. ILUSTRATES USE OF ROUTINE PASS.
C ASSUMES THERE ARE ALWAYS AT LEAST TWO MEASURED VALUES PER INDIV. REC.
C DATREC(3)=TIME DATA ITEM
C DATREC(4)=INDEPENDENT VARIABLE DATA ITEM
C DATREC(5)=MISSING INDEPENDENT VARIABLE DATA ITEM
C =0 INDEP VAR NOT MISSING
C =1 IF FIRST DATA RECORD OF INDIVIDUAL RECORD IS MISSING INDEP VAR
C =3 IF LAST DATA RECORD OF INDIVIDUAL RECORD IS MISSING INDEP VAR
C =2 OTHERWISE
C
SUBROUTINE INFN (ICALL,THETA,DATREC,INDXS,NEWIND)
DIMENSION THETA(*),DATREC(*),INDXS(*)
DOUBLE PRECISION THETA
DIMENSION U(1000),V(1000)
IF (ICALL.EQ.3) RETURN
I=0
C INITIALIZE PASS
MODE=0
CALL PASS (MODE)
MODE=2
C PASS THROUGH DATA
5 CALL PASS (MODE)
IF (MODE.EQ.0) GO TO 10
C IF INDEP VAR IS PRESENT, STORE TIME AND VALUE
IF (DATREC(5).EQ.0.) THEN
I=I+1
U(I)=DATREC(3)
V(I)=DATREC(4)
ENDIF
GO TO 5
10 I=0
C INITIALIZE PASS A SECOND TIME
MODE=0
CALL PASS (MODE)
MODE=2
C PASS THROUGH DATA A SECOND TIME
15 CALL PASS (MODE)
IF (MODE.EQ.0) RETURN
C IF INDEP VAR IS MISSING, STORE INTERPOLATED VALUE
IF (DATREC(5).EQ.0.) THEN
I=I+1
ELSE
IF (DATREC(5).EQ.1) THEN
K=I+1
L=I+2
ELSEIF (DATREC(5).EQ.2.) THEN
K=I
L=I+1
ELSEIF (DATREC(5).EQ.3.) THEN
K=I-1
L=I
ENDIF
A=(U(K)*V(L)+U(L)*V(K))/(U(K)-U(L))
B=(V(K)-V(L))/(U(K)-U(L))
DATREC(4)=A+B*DATREC(3)
ENDIF
GO TO 15
END
C DEFINES A 1 COMPARTMENT LINEAR MODEL WITH FIRST-ORDER ABSORPTION
C COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT
C
SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)
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 /
IDNO=1
NCM=2
NPAR=3
DO 10 J=1,7
DO 10 I=1,NCM
10 IATT(I,J)=MOD(I,J)
C SET LINK:
C K20 (KE)
LINK(2,3)=1
C K12 (KA)
LINK(1,2)=3
RETURN
END
C DEFINES A 3 COMPARTMENT MODEL
C COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT COMPT3: EFFECT COMPT
C
SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)
DIMENSION IATT(IR,*),LINK(IR,*)
INTEGER MOD(3,7)
DATA MOD/
C INITIAL STATUS: ON ON ON
X 1,1,1,
C ON/OFF ALLOWED: NO NO NO
X 0,0,0,
C DOSE ALLOWED: YES NO NO
X 1,0,0,
C DEFAULT FOR OBSERVATIONS: NO NO YES
X 0,0,1,
C DEFAULT FOR DOSES: YES NO NO
X 1,0,0,
C FUNCTION (HIGH ORDER)
X 4HDEPO,4HCENT,4HEFFE,
C FUNCTION (LOW ORDER)
X 4HT ,4HRAL ,4HCT /
NCM=3
NPAR=4
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(2,4)=2
C K23
LINK(2,3)=3
C K30 (KEO)
LINK(3,4)=4
RETURN
END
C DES FOR A 1 COMPARTMENT LINEAR MODEL WITH FIRST-ORDER ABSORPTION
C
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
C EQUATIONS FOR ABSORPTION COMPARTMENT
DADT(1)=-P(3)*A(1)
DA(1,1)=-P(3)
DP(1,3)=-A(1)
C EQUATIONS FOR CENTRAL COMPARTMENT
DADT(2)= P(3)*A(1)-P(1)*A(2)
DA(2,1)= P(3)
DA(2,2)=-P(1)
DP(2,1)=-A(2)
DP(2,3)= A(1)
RETURN
END
SUBROUTINE TOL (NRD)
DIMENSION NRD(*)
NRD(1)=4
RETURN
END
C AES FOR COMPARTMENT (3) IN EQUILLIBRIUM WITH COMPARTMENT (2)
C
SUBROUTINE AES (INIT,A,P,T,E,IR,DA,DP,DT)
DIMENSION A(*),P(*),E(*),DA(IR,*),DP(IR,*),DT(*)
DOUBLE PRECISION A,P,T,E,DA,DP,DT
IF (INIT.EQ.1) THEN
C SOLUTION FOR EQUILLIBRIUM COMPARTMENT
A(3)=P(4)*A(2)
ELSE
C EQUATIONS FOR EQUILLIBRIUM COMPARTMEMT
E(3)=A(3)-P(4)*A(2)
DA(3,2)=-P(4)
DA(3,3)=1.
DP(3,3)=-A(2)
ENDIF
RETURN
END
C DEFINES A 1 COMPARTMENT MODEL WITH DRUG DEPOT COMPARTMENT
C AND COMPARTMENT IN EQUILLIBRIUM WITH CENTRAL COMPARTMENT
C COMPT1: DRUG DEPOT COMPT2: CENTRAL COMPT COMPT3: EQUIL COMPT
C
SUBROUTINE MODEL (IDNO,NCM,NPAR,IR,IATT,LINK)
DIMENSION IATT(IR,*),LINK(IR,*)
INTEGER MOD(3,7)
DATA MOD/
C INITIAL STATUS: OFF, ON, ON
X 0,1,1,
C ON/OFF ALLOWED: YES, NO, NO
X 1,0,0,
C DOSE ALLOWED: YES, YES, NO
X 1,1,0,
C DEFAULT FOR OBSERVATIONS: NO, YES, NO
X 0,1,0,
C DEFAULT FOR DOSES: YES, NO, NO
X 1,0,0,
C FUNCTION (HIGH ORDER)
X 4HDEPO,4HCENT,4HEQUI,
C FUNCTION (LOW ORDER)
X 4HT ,4HRAL ,LBRM
C EQUILIBRIUM COMPT: NO, NO, YES
X 0,0,1
C AMOUNT EXCLUDED FROM SYSTEM INTERIOR: NO, NO, NO
X 0,0,0/
IDNO=2
NCM=3
NPAR=4
DO 10 J=1,9
DO 10 I=1,NCM
10 IATT(I,J)=MOD(I,J)
RETURN
END