Dear fellow NONMEM users,
May I ask if anyone has experience with including the prior information for
between occasion variability (BOV) for model parameter(s) using the $PRIOR
subroutine in NONMEM? In my data, subjects were dosed daily for seven doses
(loading phase) followed by weekly doses (maintenance phase) for 10 weeks.
All drug concentration measurements were taken at least one week after the
final maintenance dose. I'm trying to include BOV related to F for the second
through tenth doses versus the first dose in the maintenance phase. I'm
neglecting the BOV related to F for the second through seventh doses in the
loading phase.
When I included the prior information for BOV in the control file, NONMEM gave
me a termination error: INPUTS SPECIFIED TO ROUTINE NWPRI ARE INAPPROPRIATE.
Could I seek your opinion on where I've gone wrong?
The relevant sections of my control file are enclosed below. Data for the
first two subjects follows.
Thank you and best wishes,
Kok-Yong Seng, PhD
DSO National Laboratories
Singapore
_________________
$INPUT C ID TIME AMT CMT DOSN DV MDV WT
$DATA DATA1.CSV IGNORE=C
$PRIOR NWPRI NTHETA=11 NETA=13 NEPS=1 NTHP=9 NETP=5 NEPP=0 NPEXP=1 PLEV=0
$SUBROUTINES ADVAN5 TRANS1
$MODEL
COMP=DEPOT
COMP=CENTRAL
COMP=METAB
COMP=PERIP
COMP=METABP
$PK
;INCLUDING ALLOMETRIC SCALING FOR VOLUME & CLEARANCE
TVCL2=THETA(1)*((WT/70)**0.75)
TVV2 =THETA(2)*WT/70
TVCL3=THETA(3)*((WT/70)**0.75)
TVV3 =THETA(4)*WT/70
TVKA =THETA(5)
TVV4 =THETA(6)*WT/70
TVQ4 =THETA(7)*((WT/70)**0.75)
TVV5 =THETA(8)*WT/70
TVQ5 =THETA(9)*((WT/70)**0.75)
;RANDOM EFFECT MODEL
CL2=TVCL2*EXP(ETA(1))
V2=TVV2*EXP(ETA(2))
CL3=TVCL3*(291.82/319.87)*EXP(ETA(3))
V3=TVV3*(291.82/319.87)*EXP(ETA(4))
......
F1=1
IF(DOSN.EQ.2) F1=1*EXP(ETA(5)) ; DOSN identifies the second through tenth
dosing instances
IF(DOSN.EQ.3) F1=1*EXP(ETA(6))
IF(DOSN.EQ.4) F1=1*EXP(ETA(7))
IF(DOSN.EQ.5) F1=1*EXP(ETA(8))
IF(DOSN.EQ.6) F1=1*EXP(ETA(9))
IF(DOSN.EQ.7) F1=1*EXP(ETA(10))
IF(DOSN.EQ.8) F1=1*EXP(ETA(11))
IF(DOSN.EQ.9) F1=1*EXP(ETA(12))
IF(DOSN.EQ.10) F1=1*EXP(ETA(13))
......
$ERROR
IF (CMT.EQ.2) THEN
IPRED=LOG(A(2)/S2)
IRES=DV-IPRED
IWRES=IRES/IPRED
Y= IPRED + SQRT(THETA(10)**2)*EPS(1)
ENDIF
IF (CMT.EQ.3) THEN
IPRE=LOG(A(3)/S3)
IRES=DV-IPRE
IWRE=IRES/IPRE
Y= IPRE + SQRT(THETA(11)**2)*EPS(1)
ENDIF
; INITIAL ESTIMATES for THETAs
$THETA
(0,50)
(0,2000)
(0,50)
(0,50)
(0,10)
(0,2000)
(0,10)
(0,500)
(0,10)
(0,0.4)
(0,0.4)
; PRIOR MEAN OF THETAS
$THETA 29.3 FIX
$THETA 4220 FIX
$THETA 7.03 FIX
$THETA 40 FIX
$THETA 1.41 FIX
$THETA 5190 FIX
$THETA 20 FIX
$THETA 840 FIX
$THETA 3.6 FIX
; DEGREES OF FREEDOM FOR OMEGAS
$THETA 30 FIX
$THETA 30 FIX
$THETA 30 FIX
; INITIAL ESTIMATES for OMEGAS
$OMEGA BLOCK(3) 0.09 0.05 0.09 0.05 0.05 0.09
$OMEGA BLOCK(1) 0.05
$OMEGA BLOCK(1) 0.1 ; D2F
$OMEGA BLOCK SAME ; D3F
$OMEGA BLOCK SAME ; D4F
$OMEGA BLOCK SAME ; D5F
$OMEGA BLOCK SAME ; D6F
$OMEGA BLOCK SAME ; D7F
$OMEGA BLOCK SAME ; D8F
$OMEGA BLOCK SAME ; D9F
$OMEGA BLOCK SAME ; D10F
; PRIOR UNCERTAINTY IN OMEGAS
$OMEGA BLOCK(9)
3.47
257 67900
0.699 76.7 0.241
3.56 243 0.843 17
0.0038 15.9 -0.0153 -0.0134 0.0641
431 45800 90.7 342 1.28 250000
2.15 -8.68 0.306 2.84 -0.00718 815 6.21
37.4 10600 4.89 207 6.44 -19400 -93.5 20700
0.249 34.5 0.0588 0.518 0.0237 46 0.263 19.7 0.134 FIX
; PRIOR OMEGA VALUES
$OMEGA BLOCK(3) 0.0815 0.0721 0.161 0.0891 0.137 0.15 FIX
$OMEGA BLOCK(1) 0.773 FIX
$OMEGA BLOCK(1) 0.383 FIX
$SIGMA 1 FIX
$EST MSF=101.MSF MAXEVAL=9999 PRINT=1 NOABORT NOTHETABOUNDTEST NOOMEGABOUNDTEST
NOSIGMABOUNDTEST METHOD=0 SIGL=9 NSIG=3 POSTHOC
$COV MATRIX=R
_________________
1 0 300 1 . 0 1 64.5
1 1 300 1 . 0 1 64.5
1 2 300 1 . 0 1 64.5
1 3 300 1 . 0 1 64.5
1 4 300 1 . 0 1 64.5
1 5 300 1 . 0 1 64.5
1 6 300 1 . 0 1 64.5
1 13 300 1 1 0 1 64.5
1 27 300 1 2 0 1 64.5
1 34 300 1 3 0 1 64.5
1 41 300 1 4 0 1 64.5
1 48 300 1 5 0 1 64.5
1 55 300 1 6 0 1 64.5
1 62 300 1 7 0 1 64.5
1 69 300 1 8 0 1 64.5
1 76 300 1 9 0 1 64.5
1 83 . 2 . 4.32 0 64.5
1 83 . 3 . 4.02 0 64.5
2 0 300 1 . 0 1 61.7
2 1 300 1 . 0 1 61.7
2 2 300 1 . 0 1 61.7
2 3 300 1 . 0 1 61.7
2 4 300 1 . 0 1 61.7
2 5 300 1 . 0 1 61.7
2 6 300 1 . 0 1 61.7
2 13 300 1 1 0 1 61.7
2 20 300 1 2 0 1 61.7
2 27 300 1 3 0 1 61.7
2 34 300 1 4 0 1 61.7
2 41 300 1 5 0 1 61.7
2 48 300 1 6 0 1 61.7
2 55 300 1 7 0 1 61.7
2 62 300 1 8 0 1 61.7
2 69 300 1 9 0 1 61.7
2 76 300 1 10 0 1 61.7
2 83 . 2 . 3.54 0 61.7
2 83 . 3 . 3.2 0 61.7
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