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RE: PKPD-simulations

From: E.Olofsen
Date: Wed, 24 Jul 2013 20:51:11 +0000

Hi Markus,

If R is normally distributed, perhaps it is possible that CCL and/or BSL be=
come less or equal than zero?

Erik
________________________________
From: owner-nmusers
 of markus joerger [markus.joerger
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 I=
V topoisomerase inhibitor, and simulated different dosing regimens (model f=
or D1+8 q3w below (101.ctl / NAMI-SIM-ANC--D1+8-q3w-12.5B.csv). I encounter=
ed 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 m=
ode".
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 ha=
s 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 pr=
evious 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
markus.joerger
Phone: +41-765591070
Fax: +41-714946325

Received on Wed Jul 24 2013 - 16:51:11 EDT

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