[NMusers] unprecise estimation

From: Chiaying Lin <cylin292_at_gmail.com>
Date: Tue, 8 Sep 2015 22:32:04 +0800

Dear NMusers,
I'm a NM beginner modeling for a monoclonal antibody. Below is 12
subjects's individual predicted plot , it seems that nonlinear
elimination (Michaelis-Menten) model can fit the data well. However, when
running the control stream (two compartment models with linear and
non-linear elimination), the resulting Q THETA SE% and OMEGA SE% are quite
large even thought successful minimization.From the Correlation Matrix , I
find that THETA (1) (VMAX) and THETA(2) (KM)are highly correlated (9.67E-01).
Another problem is the .fit file can't be produced.

I have tried various error models and initial estimations, however, none
had better improvement and often got error message (error 134
or parameter estimate is near its boundary). Does re-parameterization
helpful ? or need to change to other models?

Any suggestions for solving the problems are highly appreciated.
===================================================================
THETA: VMAX KM V1 V2 Q
ETA: BSVV1
ERR: ERR
run2.3.lst -167.989 eval=237 sig=+3.5 sub=12 obs=100 CCIL=YNYN NVI2.0 PV2.0
THETA = 7.35 59.6 3.68 0.87 0.0538
ETASD = 0.0676018
ERRSD = 0.25632
THETA:se% = 8.4 22.5 5.8 32.3 80.3
OMEGA:se% = 194.5
SIGMA:se% = 20.1

MINIMIZATION SUCCESSFUL

P VAL.: 0.10E+01
 _at_
  Ttot 0:44.28 Test 0:44.28 Tcov 0 Ttcl 0:0.44

$PROBLEM BASE MODEL

$DATA ..\PKDATA.CSV IGNORE=#

$INPUT ID TIME AMT NDV=DROP LNDV=DV EVID MDV CMT BW AGE DOSE RATE DUR

$SUBROUTINE ADVAN8 TOL=6

$MODEL
COMP=(CENTRAL, DEFOBS, DEFDOSE)
COMP=(PERIPH)

$PK
TVVMAX=THETA(1)
VMAX=TVVMAX
KM=THETA(2)
TVV1=THETA(3)
V1=TVV1*EXP(ETA(1))
TVV2=THETA(4)
V2=TVV2
Q=THETA(5)
S1=V1
D1=DUR

$DES
C1=A(1)/V1
C2=A(2)/V2
DADT(1)=-VMAX*C1/(KM+C1)-(Q*C1)+(Q*C2)
DADT(2)=(Q*C1)-(Q*C2)

$ERROR
IPRED=LOG(F)
IRES=DV-IPRED
IWRES=IRES/IPRED
Y=IPRED+ERR(1)

$THETA
(0.1, 7, ) ;VMAX
(1, 57,300) ;KM
(0, 4, 6) ;V1
(0, 1, 6) ;V2
(0.001, 0.003, ) ;Q


$OMEGA
0.001 ; BSVV1


$SIGMA
0.5 ;ERR

$ESTIMATION METHOD=1 INTERACTION MAXEVALS=9999 POSTHOC NOABORT NSIG=3

$COVARIANCE UNCONDITIONAL SLOW PRINT=E

$TABLE ID TIME DV IPRED VMAX KM V1 V2 Q ETA1 NOPRINT ONEHEADER FILE=
run2.3.fit
$TABLE ID TIME AMT IPRED IWRES NOPRINT ONEHEADER FILE=sdtab1
$TABLE ID VMAX KM V1 V2 Q ETA1 NOPRINT ONEHEADER FILE=patab1
$TABLE ID BW AGE NOPRINT ONEHEADER FILE=cotab1

Received on Tue Sep 08 2015 - 10:32:04 EDT

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