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Re: Dynamic enzymatic model

From: saik.urien.svp <saik.urien>
Date: Wed, 22 Jul 2009 17:47:52 +0200

Christian

There is at least one parameter you cannot estimate in this code, this =
is V2 (volume of distribution of the metabolite)
This parameter is not identifiable because the fraction of parent drug =
that is metabolized is unknown and the volume of distribution simply =
relates the concentration to the amount in the body.

A simple usual solution is to fix V2 to a constant value near the parent =
V1 value.

Also
- it is unlikely you will be able to estimate OMEGA values for all of =
the parameters
- the initial SIGMA values are generally in the 0.3- 1 range for the =
proportional component

Saik

  ----- Original Message -----
  From: christian woloch
  To: nmusers
  Sent: Wednesday, July 22, 2009 11:45 AM
  Subject: [NMusers] Dynamic enzymatic model


  Dear all,
  I try to model simultaneously a parent drug and its metabolite using a =
2 compartments dynamic enzymatic model
  (using the general enzymatic reaction E+S-->(ES)-->E+P).
  Here is the control stream :

  $PROB TEST MODELISATION NLIN 2CPMT

  $INPUT ID TIME DV AMT MDV CMT

  $DATA DATA131.csv IGNORE=#

  $SUBROUTINE ADVAN8 TOL4 ; Modèle Non linéaire 2 cpts

  $MODEL



  COMP= (CENTRAL,DEFDOSE) ; cpt 5FU

  COMP= (CENTRAL,NODOSE) ; cpt 5FDHU

  COMP= (CENTRAL,NODOSE) ; enzyme **(1)**



  $PK



  V1 =THETA(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 métabolisation

  KE2 =THETA(6)*EXP(ETA(6)) ; Cstte de métabolisation

  ET =THETA(7)*EXP(ETA(7)) ; total enzyme

  K10=CL10/V1

  K20=CL20/V2

  S1=V1

  S2=V2



  $DES

  B= ET-A(3)

  DADT(1)= -K10 *A(1)-KE1*B*A(1)

  DADT(2)= KE2 * A(3) - K20 * A(2)

  DADT(3)= KE1 * B*A(1)-KE2*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 because of the enzyme own =
equation (DADT(3)).



  With FO, I'm trying to estimate the parameters

  But with FOCE, the run stop immediately!

  ERROR IN NCONTR WITH INDIVIDUAL 1 ID=0.10000000E+01

  NUMERICAL HESSIAN OF OBJ. FUNC. FOR COMPUTING CONDITIONAL ESTIMATE

  IS NON POSITIVE DEFINITE

  1)Are there 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 - 11:47:52 EDT

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