Dear Lu, I think you will get significantly better fits and more meaningful parameter estimates, if you do not assume that LOSS=SYNTH. SYNTH is an input rate and should have units of response per time and LOSS is a first-order rate constant with unit 1/time. These are fundamentally different parameters and should not be forced to have the same value. The ratio of SYNTH / LOSS determines your steady-state baseline in absence of drug which seems to be around 5 to 8 in this example.
The compartment value for observation of the PD response should probably be CMT.EQ.3 instead of 2. IF (CMT .EQ. 2) Q=0 In your inhibition equation, you are assuming that Imax = 1 INH=IC50/(IC50+A(1)/S1) You might consider allowing Imax to be less than 1: C=A(1)/S1 INH = 1 - Imax * C / (IC50 + C) I would consider using the FOCE(+I) method instead of FO after you have fixed the current issue. Hope it helps. Best regards Juergen ----------------------------------------------- Jurgen Bulitta, PhD, Post-doctoral Fellow Pharmacometrics, University at Buffalo, NY, USA Phone: +1 716 645 2855 ext. 281, [EMAIL PROTECTED] ----------------------------------------------- -----Ursprüngliche Nachricht----- Von: "Zheng Lu" <[EMAIL PROTECTED]> Gesendet: 28.11.07 05:53:19 An: [email protected] CC: [email protected] Betreff: [NMusers] help with indirect reponse model Dear all: With the following code and data, the predicted fit is poor and no standard error output for parameter. I highly appreciate your kind help. Thanks a lot in your busy time. $PROB PLK INDIRECT RESPONSE MODEL$INPUT ID TIME DV AMT CMT $DATA PLKDOSE10SIMUL.CSV IGNORE=C$SUBROUTINE ADVAN6 TOL=5 $MODEL COMP=(CENTRAL,DEFDOSE)COMP=PERIPH COMP=EFFECT $PK K10=THETA(1)*EXP(ETA(1))V1=THETA(2)*EXP(ETA(2)) K12=THETA(3)*EXP(ETA(3))K21=THETA(4)*EXP(ETA(4)) SYNTH=THETA(5)*EXP(ETA(5)) LOSS=SYNTH IC50=THETA(6)*EXP(ETA(6)) S1=V1 $DES DADT(1)=K21*A(2)-(K12+K10)*A(1) DADT(2)=K12*A(1)-K21*A(2) INH=IC50/(IC50+A(1)/S1) DADT(3)=SYNTH-LOSS*INH*A(3) $ERROR CP=A(1)/S1 Q=1 IF (CMT .EQ. 2) Q=0 Y=Q*F*EXP(ERR(1))+(1-Q)*F*EXP(ERR(2)) IPRE=Y $THETA (0,1.3) ;K10 (0,3) ;S1 (0,0.3) ;K12 (0,0.37) ;K21 (0,1) ;SYNTH (0,10) ;IC50 $OMEGA 0 FIX 0 FIX 0 FIX 0 FIX 0 FIX 0 FIX $SIGMA 0.040.5 $ESTIMATION MAXEVAL=9999 POSTHOC PRINT=5 $COV $TABLE NOPRINT FILE=PLKPKPD.txt ONEHEADER ID TIME AMT CMT CP IPRE CIDTIMEDVAMTCMT100168071100131050310.083344030110.08335.820310.520070110.55.23031194801118.1031232301128.99031827011815.860311630111633.390312433.750314824.190317210.43031968.0303 lu
