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De: [email protected] en nombre de [email protected]
Enviado el: vie 03/07/2009 12:53
Para: [email protected]
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: [email protected]
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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