NONMEM Users Network Archive

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Dynamic enzymatic model

From: christian woloch <c.woloch>
Date: Wed, 22 Jul 2009 09:45:56 +0000 (GMT)

Dear all, I try to model simultaneously a parent drug and its metabolite =
using a 2 compartments dynamic enzymatic model (using the general enzyma=
tic reaction E+S-->(ES)-->E+P). Here is the control stream : $PROB T=
EST MODELISATION NLIN 2CPMT $INPUT ID TIME DV AMT MDV CMT $DATA DATA131=
.csv IGNORE=# $SUBROUTINE ADVAN8 TOL4 ; Modèle Non linéaire 2 cpts=

DOSE) ; cpt 5FDHU COMP= (CENTRAL,NODOSE) ; enzyme       =
             **(1)**   $PK   V1 =THET=
A(1)*EXP(ETA(1)) ; Vd 5FU V2 =THETA(2)*EXP(ETA(2)) ; Vd 5FDHU CL10 =
=THETA(3)*EXP(ETA(3)) ; Cl d'élimination 5FU CL20 =THETA(4)*EXP(ETA=
(4)) ; Cl d'élimination 5FDHU KE1 =THETA(5)*EXP(ETA(5)) ; Cstte de m=
étabolisation KE2 =THETA(6)*EXP(ETA(6)) ; Cstte de métabolisation=

2 S1=V1 S2=V2   $DES B= ET-A(3) DADT(1)= -K10 *A(1)-K=
E1*B*A(1) DADT(2)= KE2 * A(3) - K20 * A(2) DADT(3)= KE1 * B*A(1)-K=
E2*A(3)   $ERROR IPRED=F IF (CMT.EQ.1) THEN Y=F*(1+EPS(1))+=
 EPS(2) ELSE Y=F*(1+EPS(3)) ENDIF IRES=DV-IPRED   $THETA =
(0,10,20) (0,60,100) (0,1,10) (0,1,10) (0,1,10) (0,1,10) (0,1,10) $OMEGA =
(1) (1) (1) (1) (1) (1) (1) $SIGMA (0.01) (0.01) (0.01) $EST METHOD==
1 SIG=3 MAXEVAL=9999   **(1)** : this compartment was added beca=
use of the enzyme own equation (DADT(3)).   With FO, I'm trying to es=
timate the parameters But with FOCE, the run stop immediately! ERROR IN N=
CONTR WITH INDIVIDUAL 1 ID=0.10000000E+01 NUMERICAL HESSIAN OF OBJ. FUN=
C. FOR COMPUTING CONDITIONAL ESTIMATE IS NON POSITIVE DEFINITE 1)Are th=
ere any problems in the control stream? 2)The model is overparametrized? =
Should I have to fixed parameters?   (I have over one hundred couple of=
 kinetics with 5-7 observations for each)   I would really appreciate=
 aany advice, thanks. Christian
Received on Wed Jul 22 2009 - 05:45:56 EDT

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