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simulation with nonparametric method in NONMEM

From: nele.kaessner
Date: Fri, 3 Jul 2009 12:53:50 +0200

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 Kner
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





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Received on Fri Jul 03 2009 - 06:53:50 EDT

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