PKPD-simulations
dear NONMEM community,
I built a PK-PD model (semiphysiological model for neutropenia) for a new
IV topoisomerase inhibitor, and simulated different dosing regimens (model
for D1+8 q3w below (101.ctl / NAMI-SIM-ANC--D1+8-q3w-12.5B.csv). I
encountered the problem that feedback (FEEDB) on the bone marrow has to be
increased to values >620, because otherwise it gives me:
---------------------------------------------------------------------------------------------------------
DES SUBROUTINE: ERROR IN COMPUTATION
ATTEMPT TO COMPUTE BASE**POWER WITH BASE<0.
MESSAGE ISSUED FROM SIMULATION STEP
----------------------------------------------------------------------------------------------------------
Strange enough, the same model does not produce errors in the "estimation
mode".
If I increase the time (T) for the feedback to start working out (from 500
to >/= 620 in this case), simulation works out fine:
IF(T.GE.500) THEN
FEEDB=(BASE/A(9))**GAMMA
ELSE
FEEDB=1
ENDIF
>>Time=500 is the time of first chemotherapy dosing (after the "system has
been filled with neutrophils").
Subsequently, I added "categorical ANC-toxicity" according to the following
coding:
FLAG1=0
IF (T.GT.520.AND.ANC.LT.0.5) FLAG1=1
DADT(12)=FLAG1
TBTH=A(12)
IF(A(12).GT.120) THEN
DLT=1
ELSE
DLT=0
ENDIF
This produces "differential equations" errors at about n=150, meaning it is
possible to simulate 150 patients, but not more. So far, I was not able to
identify the problem, although the same coding worked just fine for a
previous model of paclitaxel. Any help would be very welcome!
thanks and best regards
Markus
MODEL-101
;Project Name: namitecan
;Project ID: NO PROJECT DESCRIPTION
$PROB RUN# 100D (NAMI)
$INPUT C=DROP ID TIME AMT RATE DV CMT
MDV EVID
$DATA NAMI-SIM-ANC-D1+8-q3w-12.5B.CSV IGNORE=C
$SUBROUTINES ADVAN6 TOL=2
$ABBREVIATED COMRES=1
$MODEL COMP=(CENTRAL,DEFDOSE) ;1
COMP=(PER1) ;2
COMP=(PER2) ;3
COMP=(AUC) ;4
COMP=(PROL) ;5
COMP=(TRANS1) ;6
COMP=(TRANS2) ;7
COMP=(TRANS3) ;8
COMP=(ANC) ;9
COMP=(NADIR) ;10
COMP=(TNAD) ;11
COMP=(TBTH) ;12
$PK
" FIRST
" COMMON/PRCOMG/IDUM1,IDUM2,IMAX,IDUM4,IDUM5
" INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5
" IMAX=100000000
IF(ICALL.EQ.4.AND.NEWIND.NE.2) THEN
CALL RANDOM (2,R)
CCL=90+12*R
CALL RANDOM (3,R)
BSL=5+0.5*R
ENDIF
TVCL=THETA(1)*(CCL/90)**THETA(7)
CL=TVCL*EXP(ETA(1))
V1=THETA(2)
Q1=THETA(3)*EXP(ETA(2))
V2=THETA(4)*EXP(ETA(3))
Q2=THETA(5)*EXP(ETA(4))
V3=THETA(6)
K10=CL/V1
K12=Q1/V1
K21=Q1/V2
K13=Q2/V1
K31=Q2/V3
MTT=THETA(8)*EXP(ETA(5))
SLOPE=THETA(9)*EXP(ETA(6))
BASE=EXP(LOG(BSL)+THETA(10)*ETA(7))
GAMMA=THETA(11)
V1=0.15
V2=38
V3=152
S1=V1
F5=BSL
V5=1
V6=1
V7=1
V8=1
V9=1
TIJD=TIME-500
$DES
C1=A(1)/S1
DADT(1)=-K12*A(1)+K21*A(2)-K13*A(1)+K31*A(3)-K10*A(1)
DADT(2)=K12*A(1)-K21*A(2)
DADT(3)=K13*A(1)-K31*A(3)
DADT(4)=A(1)/S1
AUC=A(4)
C9=A(9)
ANC=A(9)
IF(T.GE.520) THEN
FEEDB=(BASE/A(9))**GAMMA
ELSE
FEEDB=1
ENDIF
KTR=4/MTT
KPROL=(KTR*FEEDB)-KTR*(SLOPE*C1)
DADT(5)=KPROL*A(5)-KTR*A(5)
DADT(6)=KTR*A(5)-KTR*A(6)
DADT(7)=KTR*A(6)-KTR*A(7)
DADT(8)=KTR*A(7)-KTR*A(8)
DADT(9)=KTR*A(8)-KTR*A(9)
IF(T.EQ.0) COM(1)=0
IF(COM(1).EQ.0.AND.DADT(9).LT.0.OR.T.LE.520) THEN
DADT(10)=DADT(9)
DADT(11)=1
ELSE
DADT(10)=0
COM(1)=1
DADT(11)=0
ENDIF
NADI=A(10)
TNAD=A(11)-500
;categorical ANC-toxicity
FLAG1=0
IF (T.GT.520.AND.ANC.LT.0.5) FLAG1=1
DADT(12)=FLAG1
TBTH=A(12)
IF(A(12).GT.120) THEN
DLT=1
ELSE
DLT=0
ENDIF
$ERROR
IF(DV.EQ.0) THEN
IPRED=-3
ELSE
IPRED=LOG(F)
ENDIF
Y=IPRED+THETA(10)*EPS(1)
W=IPRED
IRES=DV-IPRED
IWRES=IRES/W
$THETA
0.149 ;1 CL
0.15 ;2 V1
68.8 ;3 Q1
38 ;4 V2
0.654 ;5 Q2
152 ;6 V3
1.09 ;7 CLL>CL
115 ;8 MTT
0.888 ;9 SLOPE
0.689 ;10 ERR
0.222 ;11 GAMMA
$OMEGA
0.567 ;1 CL
0.0975 ;2 Q1
0.169 ;3 V2
0.368 ;4 Q2
0.0257 ;[P] 5 ;MTT
0.232 ;[P] 6 ;SLOPE
1 ;[P] 7 ;ERR BSL
$SIGMA
1 ;[P] PD
$SIMULATION(48532) (2453) (19923) ONLYSIMULATION
$TABLE ID TIJD IPRED PRED C9 CMT SLOPE AUC CCL BSL
NADI TNAD COM(1) TBTH DLT NOPRINT ONEHEADER FILE=101.TAB
NAMI-SIM-ANC--D1+8-q3w-12.5B.csv
C NAMI
C ID TIME AMT RATE DV CMT MDV EVID
1 0 1 1 0 5 1 4
1 500 26.5 13.3 0 1 1 1
1 500
0 9 1 2
1 524
0 9 1 2
1 548
0 9 1 2
1 572
0 9 1 2
1 596
0 9 1 2
1 620
0 9 1 2
1 644
0 9 1 2
1 668 26.5 13.3 0 1 1 1
1 668
0 9 1 2
1 692
0 9 1 2
1 716
0 9 1 2
1 740
0 9 1 2
1 764
0 9 1 2
1 788
0 9 1 2
1 812
0 9 1 2
1 836
0 9 1 2
1 860
0 9 1 2
1 884
0 9 1 2
1 908
0 9 1 2
1 932
0 9 1 2
1 956
0 9 1 2
1 980
0 9 1 2
1 1004
0 9 1 2
1 1028
0 9 1 2
1 1052
0 9 1 2
1 1076
0 9 1 2
1 1100
0 9 1 2
1 1124
0 9 1 2
1 1148
0 9 1 2
1 1172
0 9 1 2
1 1196
0 9 1 2
--
Markus Joerger MD-PhD
Medical Oncology&Clinical Pharmacology
Department of Internal Medicine
Kantonsspital
St. Gallen
Switzerland
[email protected]
Phone: +41-765591070
Fax: +41-714946325