Need help
From: "Bonhomme Vincent" vincent.bonhomme@chrcitadelle.be
Subject: [NMusers] Need help
Date: Thu, May 19, 2005 9:30 am
Dear nonmem users,
I am new to the use of nonmem and currently trying to model both PK and
PD of a medication we gave to volunteers as a continuous intravenous infusion.
We sampled blood twelve times at 8 min intervals for each subject. The
continous infusion started immediately after the first sample and its
duration varied randomly along the sequence of the remaining 11 measurements.
A measure of the pharmacodynamic effect of this medication was performed
concomittently to blood sampling. I first tried to obtain pharmacokinetic
parameters using the following data and control records (existing models in
the litterature are two compartments models):
ID TIME AMT RATE CP MDV RCBF WT
1 0 . . 1.27 0 3.09 65
1 8 480 6 . 1 . .
1 8 . . 0.89 0 7.53 65
1 16 . . 62.52 0 2.27 65
1 24 . . 166.80 0 0.76 65
1 32 . . 319.33 0 -0.99 65
1 40 . . . 1 -1.53 65
1 48 . . 824.93 0 -0.91 65
1 56 . . 1295.18 0 0.83 65
1 64 . . 1339.19 0 -7.60 65
1 72 . . 1456.10 0 -3.84 65
1 80 . . 1537.57 0 -1.92 65
1 88 . . 1336.66 0 2.33 65
2 0 . . 3.51 0 10.85 54
2 8 560 10 . 1 . .
2 8 . . 14.05 0 6.47 54
2 16 . . 112.83 0 2.04 54
etc...
$PROB TWO COMPARTMENTS / ALL SUBJECTS
$INPUT ID TIME AMT RATE CP=DV MDV RCBF=DROP WT
$DATA DATACLO
$SUBROUTINE ADVAN3 TRANS3
$PK
TVCL=THETA(1)*WT
CL=TVCL*EXP(ETA(1))
TVV=THETA(2)*WT
V=TVV*EXP(ETA(2))
TVQ=THETA(3)*WT
Q=TVQ*EXP(ETA(3))
TVVSS=THETA(4)*WT
VSS=TVVSS*EXP(ETA(4))
S1=V
$THETA (.01,4.6,8.) (.1,3.,6.) (.1,2.,4.) (.1,4.,8.) (0,.5,1) (0,50)
$OMEGA .1 .1 .1 .1
$ERROR
CALLFL=0
W = THETA(5)*EPS(1) + THETA(6)*F*EPS(2)
Y=F+W
IPRED=F
IRES=DV-IPRED
IWRES=IRES/W
$SIGMA 1 FIX 1 FIX
$ESTIMATION MAXEVALS=9999 PRINT=99 METHOD=0 NOABORT POSTHOC
$COVARIANCE
$TABLE ID CL V Q VSS IPRED IWRES NOPRINT FILE=TABLE1
$TABLE ID TIME ETA1 ETA2 ETA3 ETA4
$SCATTER PRED VS DV UNIT
$SCATTER PRED VS TIME
$SCATTER WRES VS PRED
$SCATTER IWRES VS IPRED
I let nonmem run for more than 5 days but nothing came out.
Concerning the pharmacodynamic aspects, I used the following records, let
nonmem run for the same delay and, again, did not succeed to obtain results:
ID TIME AMT RATE CP MDV RCBF WT
1 0 . . 1.27 0 3.09 65
1 8 480 6 . 1 . .
1 8 . . 0.89 0 7.53 65
1 16 . . 62.52 0 2.27 65
1 24 . . 166.80 0 0.76 65
1 32 . . 319.33 0 -0.99 65
1 40 . . . 0 -1.53 65
1 48 . . 824.93 0 -0.91 65
1 56 . . 1295.18 0 0.83 65
1 64 . . 1339.19 0 -7.60 65
1 72 . . 1456.10 0 -3.84 65
1 80 . . 1537.57 0 -1.92 65
1 88 . . 1336.66 0 2.33 65
2 0 . . 3.51 0 10.85 54
2 8 560 10 . 1 . .
2 8 . . 14.05 0 6.47 54
etc ...
$PROBLEM CMAX
$INPUT ID TIME AMT RATE CP=DROP MDV RCBF=DV WT=DROP
$DATA DATACLOKE0
$SUBROUTINES ADVAN=6 TRANS=1 TOL=6
$MODEL
COMP = CENTRAL
COMP = EFFECT
COMP = CMAX
COMP = TMAX
$PK
TVK = THETA(1)
K = TVK*EXP(ETA(1))
TVKE0 = THETA(2)
KE0 = TVKE0*EXP(ETA(2))
TVTMAX = (LOG(TVK)-LOG(TVKE0))/(TVK-TVKE0)
TMAX = TVTMAX*EXP(ETA(3))
$DES
DADT(1) = -K*A(1)
D2 = KE0*(A(1)-A(2))
DADT(2) = D2
IF (D2.GT.0) THEN
DADT(3) = D2
DADT(4) = 1
ELSE
DADT(3) = 0
DADT(4) = 0
ENDIF
$THETA
0.01
0.03
$ERROR
Y1 = A(1)
Y2 = A(2)
Y3 = A(3)
Y4 = A(4)
Y = Y2*(1+EPS(1))
$OMEGA .001 .001 .001
$SIGMA .001
$ESTIMATION METHOD=0 MAXEVAL=9999 NOABORT
$TABLE FILE=stream NOPRINT NOHEADER TIME AMT RATE MDV Y1 Y2 Y3 Y4 TMAX
Can anyone tell me if I chose the right models or help me resolving this?
Thanks in advance,
Vincent.
[Vincent Bonhomme]
E-Mail: vincent.bonhomme@chrcitadelle.be