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RE: Dynamic enzymatic model

From: Gibiansky, Ekaterina <Ekaterina.Gibiansky>
Date: Wed, 22 Jul 2009 11:01:08 -0400

Christian,
 
Is this infusion or oral dosing? If infusion, you need RATE data item, =
if oral, you need absorption compartment.
 
Also, there is a problem with volumes. If A(1 ) and A(2) are amounts and =
A(3) is concentration of the complex, you need to multiply KE2 * A(3) by =
V3 in equation 2. And divide KE1 * B*A(1) by V1 in equation 3.
 
Also, the enzyme reaction is happening in the same volume, so V1, V2 and =
V3 should be the same. And computations should be in molar amounts =
(scaling parameters can take care of this if AMT and DV are not in molar =
units).
 
Regards,
Katya
 
-------------------------------------
Ekaterina Gibiansky, PhD
Senior Scientific Director, PKPD, Modeling & Simulation
ICON Development Solutions
Email: Ekaterina.Gibiansky
<mailto:Ekaterina.Gibiansky

 

________________________________

From: owner-nmusers
On Behalf Of christian woloch
Sent: Wednesday, July 22, 2009 5:46 AM
To: nmusers
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

 

 



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Received on Wed Jul 22 2009 - 11:01:08 EDT

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