unsuscribe ________________________________
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 ---------------------------------------------------------------------- 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. ----------------------------------------------------------------------
