From: Lopez Pintor, Elsa <*elsa.lopez*>

Date: Wed, 8 Jul 2009 10:46:49 +0200

unsuscribe

________________________________

De: owner-nmusers

Enviado el: vie 03/07/2009 12:53

Para: nmusers

Asunto: [NMusers] simulation with nonparametric method in NONMEM

Dear all,

I have a question concerning the nonparametric estimation in NONMEM. I =

used the nonparametric method for phase I single dose PK data because =

parameters seemed not to be normally distributed. The dataset contained =

40 subjects and each received 3 different doses. The model fit the data =

well, and as a last evaluation I wanted to simulate 500 new subjects for =

each dose level and compare the simulations to the observed values (in a =

spaghetti plot which includes all simulated profiles as =

half-transparent, which enables the identification of concentrations =

which are repeated more often than others, as the respective area is =

darker). For comparison, I wanted to use the IPRED values and disregard =

the residual error component. What puzzled me when I saw the plot was =

that I did only see as many lines as I had subjects in the trial. So my =

question is: If I only have a limited number of subjects, does it make =

sense to use a nonparametric method at all, because the simulations I =

get from this seem to be a bit limited? Do I only get the exact =

parameter combination as I have already observed with my subjects, or =

can a nonparametric method also simulate other parameter combinations =

(in my case I have IIV on three different parameters)? The used model =

code is shown below.

Thanks and best regards

Nele

$MODEL COMP=(GUT) COMP=(CENTRAL) COMP=(PERIPH) =

COMP=(BINDING)

;

$PK

JD=DEN_

DN1=CDEN_(1)

DN2=CDEN_(2)

DN3=CDEN_(3)

;

TVCL=THETA(1)

CL=TVCL*EXP(ETA(1))

TVV2=THETA(2)

V2=TVV2*EXP(ETA(3))

TVQ=THETA(3)

Q=TVQ

TVV3=THETA(4)

V3=TVV3

TVKA=THETA(5)

KA=TVKA

TVF1=THETA(6)

F1=TVF1*EXP(ETA(2))

TVLAG=THETA(7)

ALAG1=TVLAG

TVK1=THETA(8)

K1=TVK1

TVK2=THETA(9)

K2=TVK2

TVBMAX=THETA(10)

BMAX=TVBMAX

S2=V2

K23=Q/V2

K32=Q/V3

K20=CL/V2

$DES

DADT(1)=-KA*A(1)

DADT(2)= =

KA*A(1)-K23*A(2)+K32*A(3)-K20*A(2)-K1*A(2)*(BMAX-A(4))+K2*A(4)

DADT(3)= K23*A(2)-K32*A(3)

DADT(4)= K1*A(2)*(BMAX-A(4))-K2*A(4)

;

$ERROR

IPRED=F

DEL=0

IF (IPRED.EQ.0) DEL=0.0001

W=F

IRES=DV-IPRED

IWRES=IRES/(W+DEL)

Y=F+SQRT(THETA(12)*THETA(12)+THETA(11)*THETA(11)*F**2)*EPS(1)

$MSFI=msfb1

$SIMULATION (12245) (123456 NONPARAMETRIC) ONLYSIM TRUE=FINAL

SUBPROBLEMS=500

$TABLE ID TIME TAD DOSE DV IPRED NOPRINT ONEHEADER FILE=simtab073 =

______________________________________________________________

Dr. Nele Käßner

Pharmacometrics -- Modeling and Simulation

Nycomed GmbH

Byk-Gulden-Str. 2

D-78467 Konstanz, Germany

Fon: (+49) 7531 / 84 - 4759

Fax: (+49) 7531 / 84 - 94759

mailto: nele.kaessner

http://www.nycomed.com

County Court: Freiburg, Commercial Register HRB 701257

Chairman Supervisory Board: Charles Depasse

Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders =

Ullman

----------------------------------------------------------------------

Proprietary or confidential information belonging to Nycomed Group may

be contained in this message. If you are not the addressee indicated

in this message, please do not copy or deliver this message to anyone.

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represent the opinion of the sender and do not necessarily represent

or reflect the views and opinions of the employer.

----------------------------------------------------------------------

Received on Wed Jul 08 2009 - 04:46:49 EDT

Date: Wed, 8 Jul 2009 10:46:49 +0200

unsuscribe

________________________________

De: owner-nmusers

Enviado el: vie 03/07/2009 12:53

Para: nmusers

Asunto: [NMusers] simulation with nonparametric method in NONMEM

Dear all,

I have a question concerning the nonparametric estimation in NONMEM. I =

used the nonparametric method for phase I single dose PK data because =

parameters seemed not to be normally distributed. The dataset contained =

40 subjects and each received 3 different doses. The model fit the data =

well, and as a last evaluation I wanted to simulate 500 new subjects for =

each dose level and compare the simulations to the observed values (in a =

spaghetti plot which includes all simulated profiles as =

half-transparent, which enables the identification of concentrations =

which are repeated more often than others, as the respective area is =

darker). For comparison, I wanted to use the IPRED values and disregard =

the residual error component. What puzzled me when I saw the plot was =

that I did only see as many lines as I had subjects in the trial. So my =

question is: If I only have a limited number of subjects, does it make =

sense to use a nonparametric method at all, because the simulations I =

get from this seem to be a bit limited? Do I only get the exact =

parameter combination as I have already observed with my subjects, or =

can a nonparametric method also simulate other parameter combinations =

(in my case I have IIV on three different parameters)? The used model =

code is shown below.

Thanks and best regards

Nele

$MODEL COMP=(GUT) COMP=(CENTRAL) COMP=(PERIPH) =

COMP=(BINDING)

;

$PK

JD=DEN_

DN1=CDEN_(1)

DN2=CDEN_(2)

DN3=CDEN_(3)

;

TVCL=THETA(1)

CL=TVCL*EXP(ETA(1))

TVV2=THETA(2)

V2=TVV2*EXP(ETA(3))

TVQ=THETA(3)

Q=TVQ

TVV3=THETA(4)

V3=TVV3

TVKA=THETA(5)

KA=TVKA

TVF1=THETA(6)

F1=TVF1*EXP(ETA(2))

TVLAG=THETA(7)

ALAG1=TVLAG

TVK1=THETA(8)

K1=TVK1

TVK2=THETA(9)

K2=TVK2

TVBMAX=THETA(10)

BMAX=TVBMAX

S2=V2

K23=Q/V2

K32=Q/V3

K20=CL/V2

$DES

DADT(1)=-KA*A(1)

DADT(2)= =

KA*A(1)-K23*A(2)+K32*A(3)-K20*A(2)-K1*A(2)*(BMAX-A(4))+K2*A(4)

DADT(3)= K23*A(2)-K32*A(3)

DADT(4)= K1*A(2)*(BMAX-A(4))-K2*A(4)

;

$ERROR

IPRED=F

DEL=0

IF (IPRED.EQ.0) DEL=0.0001

W=F

IRES=DV-IPRED

IWRES=IRES/(W+DEL)

Y=F+SQRT(THETA(12)*THETA(12)+THETA(11)*THETA(11)*F**2)*EPS(1)

$MSFI=msfb1

$SIMULATION (12245) (123456 NONPARAMETRIC) ONLYSIM TRUE=FINAL

SUBPROBLEMS=500

$TABLE ID TIME TAD DOSE DV IPRED NOPRINT ONEHEADER FILE=simtab073 =

______________________________________________________________

Dr. Nele Käßner

Pharmacometrics -- Modeling and Simulation

Nycomed GmbH

Byk-Gulden-Str. 2

D-78467 Konstanz, Germany

Fon: (+49) 7531 / 84 - 4759

Fax: (+49) 7531 / 84 - 94759

mailto: nele.kaessner

http://www.nycomed.com

County Court: Freiburg, Commercial Register HRB 701257

Chairman Supervisory Board: Charles Depasse

Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders =

Ullman

----------------------------------------------------------------------

Proprietary or confidential information belonging to Nycomed Group may

be contained in this message. If you are not the addressee indicated

in this message, please do not copy or deliver this message to anyone.

In such case, please destroy this message and notify the sender by

reply e-mail. Please advise the sender immediately if you or your

employer do not consent to Internet e-mail for messages of this kind.

Opinions, conclusions and other information in this message that

pertain to the sender's employer and its products and services

represent the opinion of the sender and do not necessarily represent

or reflect the views and opinions of the employer.

----------------------------------------------------------------------

Received on Wed Jul 08 2009 - 04:46:49 EDT