Problems with PD Modelling
Hi all,
I'm new to nonmem and would be grateful for some pointers and help. I'm
trying to do a pk-pd sequential modelling. I have modelled the PK data but
I've encountered problems with PD. My PD model is a indirect inhibition
response model. I have tried to change my initial estimates reduce the
number of parameters in the model, but nothing seem to get me a good
convergence. At different times, NONMEM gives me different error messages
such as "parameter estimates near its boundary", "Minimisation successful.
However problems occured with the minimization"(blank entries for omega or
sigma estimates in the results file) *** or the "r matrix is algorithmically
singular and non-positive definite". I have a few questions:
1) Are there any errors in the way I input my control and data file?
2) Under $ERROR in the control file, did I define it correctly with
EFF=A(4), Y**=EFF+EFF*ERR(1)+ERR(2)*? Or should it be IPRED=F,
Y=F+F*ERR(1)+ERR(2).
3) Why are they no estimates for sigma and omega in the results file? I have
been constantly changing my initial estimates for omega and sigma but they
always give me nil results.
I appreciate any help on this matter. Thanks!
Regards,
X.Y. Ng
*
This is an example of my control file:
$PROB RUN# pd_3_advan6
$INPUT ID TIME DV AMT CMT ADDL II MDV V2I V3I QI CLI KAI
$DATA FINAL2.2.CSV IGNORE=C
$SUBROUTINES ADVAN6 TRANS1 TOL=3
$MODEL
COMP=DEPOT
COMP=CENTRAL
COMP=PERIPH
COMP=EFFECT ;$MODEL defines the no of compartments in the model
$PK
V2=V2I
V3=V3I
Q=QI
CL=CLI
KA=KAI
S2=V2
S3=V3
KIN=THETA(1)*EXP(ETA(1))
KOUT=THETA(2)*EXP(ETA(2))
IC50=THETA(3)*EXP(ETA(3))
F4=KIN/KOUT
$DES
DADT(1)=-KA*A(1)
DADT(2)=KA*A(1)-Q/V2*A(2)+Q/V3*A(3)-CL/V2*A(2)
DADT(3)=-Q/V3*A(3)+Q/V2*A(2)
INH =A(2)/(IC50+A(2))
DADT(4)=KIN*(1-INH)-KOUT*A(4)
$ERROR
CP2=A(2)/S2
CP3=A(3)/S3
;IPRED=F
EFF=A(4)
Y=EFF+EFF*ERR(1)+ERR(2)
$THETA (0,0.281) ;POPKin
$THETA (0,0.003) ;POPkout
$THETA (0,2) ;POPIC50
$OMEGA 0.003 ;BSV Kin
$OMEGA 0.003 ;BSV Kout
$OMEGA 0.003 ;BSV IC50
$SIGMA 0.01 ;ERRCCV
$SIGMA 0.0015 ;ERRADD
$ESTIMATION METHOD=1 INTERACTION NOABORT MAXEVAL=9990 PRINT=10 POSTHOC
$COVARIANCE
$TABLE ID TIME DV AMT CMT NOPRINT ONEHEADER FILE=pd_3_advan6.TAB
and an example of my data:
* CID TIME DV AMT CMT ADDL II MDV V2I V3I QI CLI KAI 101 0 0 100 1 2 8 1
44.55 11.78 1.07 3.37 0.62 101 0 0 1 4 0 0 1 44.55 11.78 1.07 3.37 0.62
101 3 243 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101 7 293 0 4 0 0 0 44.55
11.78 1.07 3.37 0.62 101 11 261 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101
15 260 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101 19 277 0 4 0 0 0 44.55
11.78 1.07 3.37 0.62 101 23 290 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101
35 233 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101 39 271 0 4 0 0 0 44.55
11.78 1.07 3.37 0.62 101 43 274 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 101
47 276 0 4 0 0 0 44.55 11.78 1.07 3.37 0.62 *
*