NONMEM Users Network Archive

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computational issues preventing COV

From: markus joerger <markus.joerger>
Date: Sun, 14 Feb 2010 11:23:46 +0100

dear NONMEM community,

The following MESSAGE:

MINIMIZATION SUCCESSFUL
HOWEVER, PROBLEMS OCCURRED WITH THE MINIMIZATION.
REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND ACCEPT THEM ONLY
AFTER CHECKING THAT THE COVARIANCE STEP PRODUCES REASONABLE OUTPUT.

...has already been discussed in 2008, and seems to be a computational issue
preventing successful COV (Prof. Nick Holford). I encounter the same problem
with an i.v. Gemcitabine model. COV is successful with GEM and its
metabolite dFdU. However, if I add intracellular triphosphates (dFdCTP),
minimisation is just fine, but no COV. This has persisted after attempts to
simplify model or computation (e.g. fixing ETAs, using just one EPS,
introducing simulated PK-curves (based on PK-estimates) back into the
model). Mass-transport to triphosphate-CMPT is intentionally fixed very low
(low concentrations), and volume-of-distribution of intracellular
triphosphates scaled to V1.

Thanks for support,

kind regards, Markus


--
Markus Joerger MD PhD
Department of Medical Oncology
Rorschacherstr. 95
9007 St. Gallen
markus.joerger
markus.joerger
phone: +41-765591070
fax: +41-714946368


CONTROL STREAM:
------------------------------
---------------------------------------------------------------------------------------------

$DATA MO5_gem33.CSV IGNORE=C
$SUBROUTINES ADVAN5
$MODEL COMP=(GEM) COMP=(P1) COMP=(dFdU) COMP(dFdCTP)

$PK

 TVCL1=THETA(1)
 CL1=TVCL1*EXP(ETA(1))

 TVV1=THETA(2)
 V1=TVV1*EXP(ETA(2))

 TVQ1=THETA(3)
 Q1=TVQ1*EXP(ETA(3))

 TVV2=THETA(4)
 V2=TVV2*EXP(ETA(4))

 TVCL2=THETA(5)
 CL2=TVCL2*EXP(ETA(5))

 TVV3=THETA(6)
 V3=TVV3*EXP(ETA(6))

 TVK40=THETA(7)
 K40=TVK40*EXP(ETA(7))

 K12=Q1/V1
 K21=Q1/V2
 K13=CL1/V1
 K30=CL2/V3

 RF=THETA(8)

 K14=0.000001*K13
 V4=K14*RF*V1/K13

 S1=V1/1000
 S3=V3/1000
 S4=V4/1000

$ERROR CALLFL=0
 IPRE=-3
 FLG1=0
 FLG3=0
 FLG4=0
 IF(CMT.EQ.1)FLG1=1
 IF(CMT.EQ.3)FLG3=1
 IF(CMT.EQ.4)FLG4=1
 IF(F.GT.0) IPRE=LOG(F)
 Y=LOG(F)+EPS(1)*FLG1+EPS(2)*FLG3+EPS(3)*FLG4
 W=LOG(F)
 IRES=DV-IPRE
 IWRES=IRES/W

$THETA
(0,163) ;CL-gemcitabine.1
(0,11.9) ;V1.2
(0,95.1) ;Q1.3
(0,20) ;V2.4
(0,14.1) ;CL-dFdU.5
(0,28) ;V3.6
(0,0.21) ;K40.7
(0,646) ;RF.8

$OMEGA
 0.37 ;CL1.1
 0.23 ;V1.2
 0.0094 ;Q1.3
 0.036 ;V2.4
 0.14 ;CL2.5
 0.14 ;V3.6
 0.27 ;K40.9.7

$SIGMA
 0.07 ;IIV-1
 0.0355 ;IIV-3
 0.757 ;IIV-4

$ESTIMATION PRINT=5 MAXEVAL=3000 METHOD=1
  NOABORT POSTHOC SIGDIG=3 MSFO=MSF004BBAB

Received on Sun Feb 14 2010 - 05:23:46 EST

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