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The following message was posted to: PharmPK
Dear all,
I am trying to simultaneously fit in vivo tumor growth data obtained in
the absence and presence of daily doses of a tumor inhibitor in
WinNonlin. It was
tried to circumvent the time-tedious writing of dose/time data into the
model-parameter window by implementing the PK functions in a do...next
loop
(printed in bold). However, this doesn't work - WNL fits all data points
regardless of dosing, i.e. dosing is ignored and all tumor growth curves
are superimposed. I checked this by directly putting a single dose into
the differential equations as a start parameter, and in that case the PD
curves were different depeding on dose. Does anyone have an idea how to
program this correctly? As my experiences with user models in Winnonlin
are also limited, is the rest of the code concerning the PK correct? Do
the differential equations have to appear in the do-loop, or do they
have
to be in the same place as the ones for PD?
The model assumes linear tumor growth ("kin") with a start tumor area
"wo". The pontency of the inhibitor is defined as "IC50", dtime denotes
the time of administration in hours (equal dosing scheme, every 24h, for
90 days).
Any help from more experienced users would be highly appreciated!
Thanks and best wishes
Nele
remark Multiple dosing: Tumor area + plasma conc. (2-cmt model, po)
remark tumor area in mm^2
remark
remark no. parameter constant secondary parameter
remark --- --------- -------- -------------------
remark 1 kin [mm^2/h] # doses
remark 2 IC50 [ug/L] dose 1 [ug/kg]
remark 3 W0 [mm^2] dose 2 [ug/kg]
remark 4 dose 3 [ug/kg]
remark 5 etc
remark ******************** WARNING *****************
remark
remark - define model-specific commands
COMMANDS
NFUNCTIONS 4
NDERIVATIVES 13
NPARAMETERS 3
NCON 4
PNAMES 'kin','IC50','W0'
END
remark - define temporary variables
TEMPORARY
T=X
dtime=0
kin = P(1)
IC50 = P(2)
W0 = P(3)
END
remark - define differential equations starting values
START
Z(1) = 0
Z(2) = 0
Z(3) = 0
Z(4) = 0
Z(5) = 0
Z(6) = 0
Z(7) = 0
Z(8) = 0
Z(9) = 0
Z(10) = W0
Z(11) = W0
Z(12) = W0
Z(13) = W0
END
remark - define differential equations
DIFFERENTIAL
ka =0.2
V2 =40
CL =10
Q =2
V3 =1
bio =1
tlag =0.5
K23=Q/V2
K32=Q/V3
K20=CL/V2
j = 4
ndose = con(1)
rema Count up the number of doses administered up to time x
do i = 1 to ndose
j = j + 1
if x <= dtime then goto red
endif
dtime=dtime+24
next
rema Adjust number of doses if x exactly equals a dosing time
red:
if x = dtime then ndose = i
else ndose=i-1
endif
do i = 1 to ndose
j = j + 1
t = x - dtime-tlag
dose1 = con(2)
dose2 = con(3)
dose3 = con(4)
INP1=0
INP2=0
INP3=0
if (x=dtime+tlag) then
INP1=dose1
INP2=dose2
INP3=dose3
endif
dz(1)= INP1-ka*z(1)
dz(2)= bio*ka*z(1)-k23*z(2)+k32*z(3)-k20*z(2)
dz(3)= k23*z(2)-k32*z(3)
dz(4)= INP2-ka*z(4)
dz(5)= bio*ka*z(4)-k23*z(5)+k32*z(6)-k20*z(5)
dz(6)= k23*z(5)-k32*z(6)
dz(7)= INP3-ka*z(7)
dz(8)= bio*ka*z(7)-k23*z(8)+k32*z(9)-k20*z(8)
dz(9)= k23*z(6)-k32*z(9)
dtime=dtime+24
next
rema growth only
DZ(10) = kin
rema growth and killing dose1
conc2=z(2)/V2
DZ(11) = kin*(1-conc2/(IC50+conc2))
rema growth and killing dose2
conc5=z(5)/V2
DZ(12) = kin*(1-conc5/(IC50+conc5))
rema growth and killing dose3
conc8=z(8)/V2
DZ(13) = kin*(1-conc8/(IC50+conc8))
END
remark - define algebraic functions
FUNCTION 1
F= Z(10)
END
FUNCTION 2
F= Z(11)
END
FUNCTION 3
F= Z(12)
END
FUNCTION 4
F= Z(13)
END
remark - end of model
EOM
--
Bayer Schering Pharma AG
Development Pharmacokinetics
Berlin, S109, 03, 306A
E-mail: nele.plock.-a-.bayerhealthcare.com
Web: http://www.bayerscheringpharma.de
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