From: Paul Baverel <*paul.baverel*>

Date: Sun, 05 Jul 2009 10:46:58 +0200

Dear Nele,

Simulating with the nonparametric option in NONMEM is performed by

sampling based on the original nonparametric distribution you obtained

by fitting your data. Therefore, values of simulated nonparametric

IPRED will all be issued from the estimated IPRED, the difference

between simulated and estimated distribution of IPRED being in the

frequency of appearance (spike height).

Hope this helps.

Paul.

Quoting nele.kaessner

*> 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
*

*>
*

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*

*> Chairman Supervisory Board: Charles Depasse
*

*> Management Board: Dr. Barthold Piening, Gilbert Rademacher, Dr. Anders
*

*> Ullman
*

*>
*

*>
*

*>
*

*>
*

*>
*

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Received on Sun Jul 05 2009 - 04:46:58 EDT

Date: Sun, 05 Jul 2009 10:46:58 +0200

Dear Nele,

Simulating with the nonparametric option in NONMEM is performed by

sampling based on the original nonparametric distribution you obtained

by fitting your data. Therefore, values of simulated nonparametric

IPRED will all be issued from the estimated IPRED, the difference

between simulated and estimated distribution of IPRED being in the

frequency of appearance (spike height).

Hope this helps.

Paul.

Quoting nele.kaessner

Received on Sun Jul 05 2009 - 04:46:58 EDT