Markus, Can you indicate us how did you define the initial conditions of the system?
Best Regards, Juanjo. On 25/07/2013, at 12:37, "[email protected]<mailto:[email protected]>" <[email protected]<mailto:[email protected]>> wrote: Hi Markus, If R is normally distributed, perhaps it is possible that CCL and/or BSL become less or equal than zero? Erik ________________________________ From: [email protected]<mailto:[email protected]> [[email protected]<mailto:[email protected]>] on behalf of markus joerger [[email protected]<mailto:[email protected]>] Sent: Wednesday, July 24, 2013 9:29 PM To: NONMEM USERS Subject: [NMusers] 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<http://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]<mailto:[email protected]> Phone: +41-765591070 Fax: +41-714946325
