[NMusers] An LSODA CODE -3 error during simulation

From: Penny Zhu <penny.zhu_at_novartis.com>
Date: Wed, 6 May 2015 12:07:13 -0700

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 - 15:07:13 EDT

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