Re: help with indirect reponse model
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