Re: [NMusers] An LSODA CODE -3 error during simulation

From: Devin Pastoor <devin.pastoor_at_gmail.com>
Date: Wed, 06 May 2015 20:53:50 +0000

Penny,

NONMEM is having trouble with it's integration routine. Likely due to the
complexity of your model.

I would suggest

1. Change the TOL down to 6 or so to see if you can get it to run.
2. and/or simplify your model.
3. (I wouldn't think it is this) but perhaps change your error to be a
little larger 0.0000000001 might have some issues with floating point
calculations but I could be incorrect here. Something like 0.0001 should
still give you negligible error for all intents and purposes.

Best of luck!


Devin Pastoor
Center for Translational Medicine
University of Maryland, Baltimore


On Wed, May 6, 2015 at 4:44 PM Penny Zhu <penny.zhu_at_novartis.com> wrote:

> Hi All
> I am running into a LSODA CODE -3 error during simulation. The error code
> is below and NONMEM script and data attached.
> Can somebody help me out? Many thanks.
>
> ############################error message
> PROBLEM NO.: 1 SUBPROBLEM NO.: 1
>
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED SIMULATION REDO
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> PRED ERROR OCCURRED TOO OFTEN ON SIMULATION
> 0PRED EXIT CODE = 1
> 0INDIVIDUAL NO. 1 ID= 4.00000000000000E+00 (WITHIN-INDIVIDUAL)
> DATA REC NO. 3
> THETA=
> 2.50E-01 1.02E+00 3.92E+01 1.47E+01 1.95E+01 6.37E-01
> 5.91E+02 1.68E+02 1.56E-01 3.55E-02
> 1.10E+00 1.24E+00 8.52E-01 -4.88E-01 2.26E-01 4.82E-01
> 9.91E-01 1.68E-01
> NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE.
> NO. OF REQUIRED SIGNIFICANT DIGITS IN SOLUTION VECTOR
> TO DIFFERENTIAL EQUATIONS, 21, MAY BE TOO LARGE.
> MESSAGE ISSUED FROM SIMULATION STEP
> #CPUT: Total CPU Time in Seconds, 0.015
> Stop Time:
> Tue May 5 21:42:47 CEST 2015
>
>
> ###########################nonmem code
> $INPUT ID,TIME,DV,AMT,RATE,EVID,MDV,CMT,RACE,AGE,WEIG
>
> $DATA sim.csv IGNORE=_at_
>
> $SUBROUTINES ADVAN13 TOL=9
>
> $MODEL
> COMP(Depot,DEFDOSE)
> COMP(Central)
> COMP(Periph)
> COMP(Periph)
> COMP(Effect,DEFOBS)
>
> $PK
>
> TVKA=THETA(1)
> KA = TVKA*EXP(ETA(1))*(AGE/64.6)**THETA(14)
>
> IF(RACE.EQ.0) ADJCL=1
> KARBC =THETA(11)
> KARHC = THETA(12)
> IF(RACE.EQ.1) ADJCL = KARBC
> IF(RACE.EQ.2) ADJCL = KARHC
> TVCL=THETA(2)
> CL = TVCL*WEIG*ADJCL*EXP(ETA(2))
>
> VCRBC=THETA(13)
> IF(RACE.EQ.0) ADJVC=1
> IF(RACE.EQ.1) ADJVC = VCRBC
> IF(RACE.EQ.2) ADJVC = 1
> TVVC = THETA(3)
> VC = TVVC*WEIG*ADJVC*EXP(ETA(3))
>
> Q = THETA(4)*WEIG
> VP = THETA(5)*WEIG
> F1 = THETA(6)
> K = CL/VC
> K12 = Q/VC
> K21 = Q/VP
>
> BASE = THETA(7)*EXP(ETA(4))
> KSS = THETA(8)
> KINT = THETA(9)
> KDEG = THETA(10)
>
>
> KIN=THETA(15)
> EC50=THETA(16)
> IMAX=THETA(17)
> LAM=THETA(18)
>
> A_0(4) = BASE
> A_0(5) = 0.54
>
> $DES
>
> CONC=0.5*(A(2)/VC-A(4)-KSS)+0.5*SQRT((A(2)/VC-A(4)-KSS)**2+4*KSS*A(2)/VC)
> ; Free drug
> KSYN = BASE*KDEG
> DADT(1) =-KA*A(1)
> ; Free Drug depot
> DADT(2) = KA*A(1)-(K+K12)*CONC*VC+K21*A(3)-KINT*A(4)*CONC*VC/(KSS+CONC)
> ; Total drug amount
> DADT(3) = K12*CONC*VC-K21*A(3)
> ; Free Drug second compartment amount
> DADT(4) = KSYN - KDEG*A(4) - (KINT-KDEG)*CONC*A(4)/(KSS+CONC)
> ; Total target
> R=A(4)*KSS/(KSS+CONC)
> DADT(5) = KIN*(1-(IMAX*CONC**LAM)/(EC50+CONC**LAM))-KIN/0.54*A(5)
> ;KOUT=KIN as baseline for effect is 1
>
>
> $ERROR
> CALLFL = 0
>
> CONC1=0.5*(A(2)/VC-A(4)-KSS)+0.5*SQRT((A(2)/VC-A(4)-KSS)**2+4*KSS*A(2)/VC)
> R1=A(4)*KSS/(KSS+CONC1)
> RTOT=A(4)
> IF(CMT.EQ.5) Y = A(5) +EPS(1)
>
> IPRED = Y
>
>
>
> $THETA
> (0.250 FIX) ;1 KA perday
> (1.02 FIX) ;2 CL 3.03*24/66 to per day to per kg
> (39 FIX) ;3 VC 2590/66kg to per kg
> (14.65 FIX) ;4 Q 40.3*24/66 to per day to per kg
> (19.54 FIX) ;5 VP 1290/66kg to per kg
> (0.637 FIX) ;6 F1
> (591 FIX) ;7 BASE ng/mL
> (168 FIX) ;8 KSS ng/mL
> (0.156 FIX) ;9 KINT 0.00652*24 to per day
> (0.03552 FIX) ;10 KDEG 0.00148*24 to per day
> (1.10 FIX) ;11 KARBC
> (1.24 FIX) ;12 KARHC
> (0.852 FIX) ;13 VCRBC
> (-0.4 FIX) ;14 AGE power
> (0.22649 FIX) ;KIN
> (0.48218 FIX) ;EC50
> (0.991 FIX) ;IMAX
> (0.8 FIX) ;LAM
>
> $OMEGA
> 0 FIX ;1 KA
> 0 FIX ;2 CL
> 0 FIX ;3 V1
> 0 FIX ;4 BASE
>
>
> $SIGMA
> 0.0000000001 FIX ;EPS(1)
>
>
> $SIMULATION SUBPROB=1 ONLYSIMULATION (11111)
>
> $TABLE ID TIME DV CMT IPRED CONC1 R1 RTOT RACE AGE WEIG EC50 KIN IMAX LAM
> NOPRINT ONEHEADER FILE=AllRecords.TXT
>
> #################data file
>
> SID Time DV Dose Rate EVID MDV
> CMT RACE AGE WEIGHT
> 4 0 0 3000000 0
> 1 1 1 0 64.6 68
> 4 0 0 0 0 0
> 0 5 0 64.6 68
> 4 7 0 0 0 0
> 0 5 0 64.6 68
> 4 28 0 0 0 0
> 0 5 0 64.6 68
> 4 56 0 0 0 0
> 0 5 0 64.6 68
> 4 84 0 0 0 0
> 0 5 0 64.6 68
> 4 112 0 0 0 0
> 0 5 0 64.6 68
> 4 140 0 0 0 0
> 0 5 0 64.6 68
> 6 0 0 6000000 0
> 1 1 1 0 64.6 68
> 6 0 0 0 0 0
> 0 5 0 64.6 68
> 6 7 0 0 0 0
> 0 5 0 64.6 68
> 6 28 0 0 0 0
> 0 5 0 64.6 68
>
> Thank you very much and best regards!
>
> Penny (Peijuan) Zhu
> Associate Director
> PD Bio-Pharma Medical Affairs
> Sandoz
> 1N025, 100 College Road West
> Princeton, NJ 08540
>
> Cell: 862-926-9079
>
>

Received on Wed May 06 2015 - 16:53:50 EDT

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