Antwort: PK/PD models to describe anti-ancer drug effect on the tumor volume
Dear Patrick,
the Simeoni model works well:
Simeoni M, Magni P, Cammia C, De Nicolao G, Croci V, Pesenti E, Germani M,
Poggesi I, Rocchetti M.
Predictive pharmacokinetic-pharmacodynamic modeling of tumor growth
kinetics in xenograft models after administration of anticancer agents.
Cancer Res. 2004 Feb 1;64(3):1094-101.
I've attached a code using this model below. My code used the
concentrations in tumor tissue, but you can just as well use the serum
concentrations.
I also develowed a second model which uses linear tumor growth and
considers resistance development over time, which is less pronounced if
concentrations of the anti-tumor drug increase. I've attached that code as
well, maybe it is useful.
Considering the predictiveness of the model, in my case it seemed like the
use of physiological life-span seemed to be a good corrector (I got the
idea from Monro, Drug Toxicokinetics: Scope and Limitations that Arise
from Species Differences in Pharmacodynamic and Carcinogenic Responses, J
Pharmacokin Biopharm 22, 41-57, 1994). I.e. if you want your patients to
survive 6 months, then use human average age of 75 years and mouse age of
2 years, so a mouse would have to survive 6 months/75*2= 5 days. But this
might be different from drug to drug.
Best wishes
Nele
Simeoni:
$SUBROUTINES ADVAN6 TOL=3
$MODEL
COMP=(GUT)
COMP=(CENTRAL)
COMP=(TUMOR)
COMP=(PD)
$PK
TVCL=THETA(1)
CL=TVCL
;
TVV2=THETA(2)
V2=TVV2
;
TVKA=THETA(3)
KA=TVKA
TVF1=THETA(4)
F1=TVF1
TVPC=THETA(5)
PC=TVPC
TVKEO=THETA(6)
KEO=TVKEO
;
TVL0=THETA(7)
L0=TVL0*EXP(ETA(1))
;
TVL1=THETA(8)
L1=TVL1
TVK2=THETA(9)
K2=TVK2
W0=THETA(10)
F4=W0
S2=V2
K20=CL/V2
S4=1
PSI=20
;
$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)
;
$DES
DADT(1)= -KA*A(1)
DADT(2)= KA*A(1) -K20*A(2)
DADT(3)= KEO*(PC*A(2)/V2 - A(3))
DADT(4)= L0*A(4)/(1+(L0/L1*A(4))**PSI)**(1/PSI)-K2*A(3)*A(4)
own code:
$SUBROUTINES ADVAN8 TOL=3
$MODEL
COMP=(GUT)
COMP=(CENTRAL)
COMP=(TUMOR)
COMP=(PD)
COMP=(AUC)
$PK
TVCL=THETA(1)
CL=TVCL*EXP(ETA(1))
;
TVV2=THETA(2)
V2=TVV2
;
TVKA=THETA(3)
KA=TVKA
TVF1=THETA(4)
F1=TVF1
TVPC=THETA(5)
PC=TVPC
TVKEO=THETA(6)
KEO=TVKEO
TVW0=THETA(7)
F4=TVW0
W0=F4 ; dataset: put a dummy dose of 1 into compartment 4, initial tumor
weight is then estimated as F4
TVKRES=THETA(8)
KRES=TVKRES
TVIC50=THETA(9)
IC50=TVIC50
TVKIN=THETA(10)
KIN=TVKIN
TVRED=THETA(13)
RED=TVRED
S2=V2
K20=CL/V2
S4=1
;
$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)
;
$DES
CAV=A(5)/(T+0.01)
RES=IC50*EXP(KRES*T*(1-CAV/(RED+CAV)))
DADT(1)= -KA*A(1)
DADT(2)= KA*A(1) -K20*A(2)
DADT(3)= KEO*(PC*A(2)/V2 - A(3))
DADT(4)= KIN*(1-A(3)/(RES+A(3)))
DADT(5)= A(3)
_________________________
Dr. Nele Plock
Bayer Schering Pharma AG
Drug Metabolism & Pharmacokinetics
Development Pharmacokinetics
Scientific Expert Development Pharmacokinetics
D- 13342 Berlin
Phone : +49-30-468 15146
Fax: +49-30-468 95146
[EMAIL PROTECTED]
http://www.bayerscheringpharma.de
Vorstand: Arthur J. Higgins, Vorsitzender | Werner Baumann, Andreas Busch,
Ulrich Köstlin, Kemal Malik, Gunnar Riemann
Vorsitzender des Aufsichtsrats: Werner Wenning
Sitz der Gesellschaft: Berlin | Eintragung: Amtsgericht Charlottenburg 93
HRB 283
Patrick Zhou <[EMAIL PROTECTED]>
Gesendet von: [EMAIL PROTECTED]
06.01.2008 20:50
An
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[NMusers] PK/PD models to describe anti-ancer drug effect on the tumor
volume
Dear NMusers,
Does anyone aware any good published example (or non-public if you are
willing to share) of modeling the anti-cancer drug effect on the tumor
volume in nude mice model? And how this is normally used in the human dose
projection, and any published work of such? Please advice. Thank you very
much.
Patrick
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