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FW: Dynamic enzymatic model

From: Gibiansky, Ekaterina <Ekaterina.Gibiansky>
Date: Fri, 31 Jul 2009 12:25:43 -0400

Christian,
 
You only need one dosing record, for CMT=1. And you do not need =
anything in the code related to dosing, Nonmem takes care of it (i.e you =
do not need Rimput=0; DUR=DOSE/RATE; IF (DUR.EQ.2) Rimput=DOSE) =
and Rimput in the $DES block).
 
Also, you cannot estimate V3 and enzyme equation does not make sense =
unless V1=V3. Also, you, probably, can not estimate V1 and V2 =
separately. I would assume all 3 compartments have the same volume.
 
And last, binding works in terms of concentrations. Concentration of =
complex is Kassociation*(A1/V)*(B/V). Then amount of complex = =
Kassociation*(A1/V)*(B/V)*V = Kassociation*A1*B/V. So, either the term =
KE1*B*A(1) in the equations should be divided by V, or your KE1 =
parameter is really Kassociation/V.
 
Regards,
Katya
 
-------------------------------------
Ekaterina Gibiansky, PhD
Senior Scientific Director, PKPD, Modeling & Simulation
ICON Development Solutions
Email: Ekaterina.Gibiansky
<mailto:Ekaterina.Gibiansky

 

________________________________

From: christian woloch [mailto:c.woloch
Sent: Monday, July 27, 2009 10:55 AM
To: Gibiansky, Ekaterina
Subject: Re : [NMusers] Dynamic enzymatic model


Hello Ekaterina,
I have forgotten to give more details about the data and the model.
- It 's an IV bolus dose (<2min)
   --> then I use the code of an infusion (RATE) as :

Rimput=0

DUR=DOSE/RATE

IF (DUR.EQ.2) Rimput=DOSE

- The model (which was implemented on Matlab first) is a 2 compartments =
with three Diff equations (DE), but for Nonmem it is a 3 one (because of =
3 DE).

As you suggested I had problem with volumes, and computation should have =
to be in molar amounts.

Then I converted all the DV and AMT in molar units (mM), considered all =
A() as amounts and a 3 compartments as and changed the ErrorBlocks as :

$PROB TEST MODELISATION NLIN 2CPMT

$INPUT ID TIME DV DOSE=AMT RATE MDV CMT

$DATA DATA17MOL.csv IGNORE=#

$SUBROUTINE ADVAN8 TOL4 ; Modèle Non linéaire 2 cpts

$MODEL

COMP= (CENTRAL,DEFDOSE) ; cpt 5FU

COMP= (CENTRAL) ; cpt 5FDHU

COMP= (CENTRAL) ; cpt Enzyme

$PK

V1 =THETA(1)*EXP(ETA(1)) ; Vd 5FU

V2 =THETA(2) *EXP(ETA(2)) ; Vd 5FDHU

CL10 =THETA(3)*EXP(ETA(3)) ; Cstte d'élimination 5FU

CL20 =THETA(4)*EXP(ETA(4)) ; Cstte d'élimination 5FDHU

CL1 =THETA(5)*EXP(ETA(5)) ; Cstte de métabolisation

CL2 =THETA(6) *EXP(ETA(6)) ; Cstte de métabolisation

ET =THETA(7)*EXP(ETA(7)) ; Quantité d'enzyme

V3 = THETA(8)*EXP(ETA(8)) ; Vd enzyme

KE1=CL1/V1

KE2=CL2/V3

K10=CL10/V1

K20=CL20/V2

S1=V1

S2=V2

S3=V3

Rimput=0

DUR=DOSE/RATE

IF (DUR.EQ.2) Rimput=DOSE

$DES

B= ET-A(3)

DADT(1)= -K10 *A(1)-KE1*B*A(1) + Rimput

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))

ELSE

Y=F*(1+EPS(2))

ENDIF

IRES=DV-IPRED

$THETA (0,10,30 ) (0,0.01,10)(0,20,100) (0,0.01,10) (0,1,5) (0,2,10) =
(0,0.001,10)(0,0.001,10)

$OMEGA (0.01) (0.01 )(0.01 )(0.01 )(0.01 ) (0.01 ) (0.01 ) (0.01 )

$SIGMA (0.3) (0.3)

$EST METHOD=0 SIG=3 MAXEVAL=9999

With this imput file

ID TIME DV AMT RATE MDV CMT
8 0 0 6.461 3.23 1 1
8 0 0 0 0 1 2
8 5 0.1855 0 0 0 1
8 5 0.0086 0 0 0 2
8 15 0.0931 0 0 0 1
8 15 0.0227 0 0 0 2
etc

Do you see a problem in this contro stream ?

(Should I have to use sclae parameters as you suggested : S1=S2=S3 =
?)

Regards Christian.

________________________________

De : "Gibiansky, Ekaterina" <Ekaterina.Gibiansky
À : nmusers
Envoyé le : Mercredi, 22 Juillet 2009, 17h01mn 08s
Objet : RE: [NMusers] Dynamic enzymatic model


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 Fri Jul 31 2009 - 12:25:43 EDT

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