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

ICON plc made the following annotations.

-------------------------------------------------------------------------=

-----

This e-mail transmission may contain confidential or legally privileged i=

nformation

that is intended only for the individual or entity named in the e-mail ad=

dress. If you

are not the intended recipient, you are hereby notified that any disclosu=

re, copying,

distribution, or reliance upon the contents of this e-mail is strictly pr=

ohibited. If

you have received this e-mail transmission in error, please reply to the =

sender, so that

ICON plc can arrange for proper delivery, and then please delete the mess=

age.

Thank You,

ICON plc

South County Business Park

Leopardstown

Dublin 18

Ireland

Registered number: 145835

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

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

ICON plc made the following annotations.

-------------------------------------------------------------------------=

-----

This e-mail transmission may contain confidential or legally privileged i=

nformation

that is intended only for the individual or entity named in the e-mail ad=

dress. If you

are not the intended recipient, you are hereby notified that any disclosu=

re, copying,

distribution, or reliance upon the contents of this e-mail is strictly pr=

ohibited. If

you have received this e-mail transmission in error, please reply to the =

sender, so that

ICON plc can arrange for proper delivery, and then please delete the mess=

age.

Thank You,

ICON plc

South County Business Park

Leopardstown

Dublin 18

Ireland

Registered number: 145835

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