Hong-Guang,
It seems you are already aware of the publications that have
demonstrated that NONMEM's warnings and failure to run the $COV step are
not of much use for model evaluation. So please stop worrying about them
and focus on more important things e.g. is your data correct (as Mark
Sale suggested).
You wrote:
"If this is the case at any time or even at most time, the NONMEM run
would not seem to be too tough."
I dont really understand what you mean. If you mean that using NONMEM is
much easier if we ignore these termination warnings then I agree with
you. Pay attention to your data and the model predictions. Dont pay
attention to these warnings that do not have any useful relationship to
the purpose of modelling.
Nick
Hong-Guang Xie wrote:
Hi Nick:
Thank you for your quick response to my inquiry email.
In my control stream (see above), the initial values for the "fixed
effects" parameters (such as f13, f15, and f16) were obtained from
each terminated run after typing and running "nmctl runname" in order
to fix a more important problem --"minimization terminated". In
addition, I used to try the *constraints* as you suggested, and
finally the minimization was still "terminated" but not "successful"
(plus, COV: NONE). If the final parameters returned from each
terminated run were used as initial values used in the $THETA section
(as seen in my last email), both "minimization terminated" and high F1
values came together. It there a good solution to the two problems at
the same time?
Your saying -- "you can ignore the rounding error and additional
problem warnings. They dont mean anything useful."-- means that we
do NOT need to care about them too much, even if minimization is
"terminated" and covariance step "aborted" or "NONE", right? My
understanding was from your abstract
(http://www.page-meeting.org/?abstract=992) and another similar
abstract (CPT, 2005; 77:p2) by Gastonguay MR et al. If this is the
case at any time or even at most time, the NONMEM run would not seem
to be too tough.
I will follow your suggestions to check if the model fits the data
well later.
Thank you,
Hong-Guang
------------------------------------------------------------------------------------------------------------------------------------------------------------
On 8/21/08, *Nick Holford* <[EMAIL PROTECTED]
<mailto:[EMAIL PROTECTED]>> wrote:
Hong-Guan,
You can ignore the rounding error and additional problem warnings.
They dont mean anything useful. You should look at your parameter
values to see if they are sensible (clearly they are not for 2 of
the bioavailibility fractions) and also use things like a VPC to
decide if the model is fitting the data (see
http://www.page-meeting.org/pdf_assets/8694-Karlsson_Holford_VPC_Tutorial_hires.pdf).
To avoid unrealistic estimates for bioavailability you can try
setting initial estimates for bioavailability fractions to
something sensible and use constraints e.g. instead of this
(0,4.93) ;f13
write this
(0,.7,1) ;f13
Nick
Hong-Guang Xie wrote:
Dear NONMEM Users,
Recently I combined six popPK studies (STDY) together as a
whole and tried to re-estimate the pop PK parameters of that
drug in the population with a wide range of the age and body
weight. In the pooled dataset, all subjects were given with a
single dose of that drug. Part of the control stream was
provided as follows. Based on the prior knowledge that a
two-compartment model with first-order absorption and
elimination is used to describe its PK profile well, a
two-compartment model was used for my meta-popPK analysis.
After the NM run for the additive or proportional error model
or both, the NM indicated that "*MIN*IMIZATION *T*ERMINATED
DUT TO ROUNDING ERRORS (ERROR=134)" alone or in combination
with "ADDITIONAL PROBLEMS OCCURED WITH THE MINIMIZATION.
REGARD THE RESULTS OF THE ESTIMATION STEP CAREFULLY, AND
ACCEPT THEM ONLY AFTER CHECKING THE COVARIANCE STEP PRODUCES
REASONABLE OUTPUT".
In addition, the typical values of the relative
bioavailability (*F1*) was estimated as 5 - 8 for STDY 3 (that
is, f13), 9 -14 for STDY 5 (or f15) and 0.4 - 0.53 for STDY 6
(f16). Obviously, only f16 seems to be reasonable. The drug
used in the STDY 3 and 5 was given extravascularly, and thus
their F1 values should be less than 1. To fix these problems,
I have made many efforts but failed. For this, I would
appreciate your time and suggestions.
Thank you,
Hong-Guang Xie
==================
............
$SUBROUTINE ADVAN4 TRANS4
$PK
ETAMX = 10
SI1=0 SI2=0
SI3=0
SI4=0
SI5=0
SI6=0
IF (STDY .EQ. 1) SI1=1 ; iv
IF (STDY .EQ. 2) SI2=1 ; iv
IF (STDY .EQ. 3) SI3=1 ; epidural
IF (STDY .EQ. 4) SI4=1 ; iv
IF (STDY .EQ. 5) SI5=1 ; rectal
IF (STDY .EQ. 6) SI6=1 ; oral
IV = SI1+SI2+SI4 ;intravascular dosing
;APPARENT CLEARANCE
TVCL=popcl
PPVCL=bsvcl
IF (ABS(PPVCL) .GE. ETAMX) EXIT 1 10 CL=TVCL*EXP(PPVCL)
;CENTRAL VOLUME OF DISTRIBUTION
TVV2=popv2
PPVV2=bsvv2
IF (ABS(PPVV2) .GE. ETAMX) EXIT 1 20
V2=TVV2*EXP(PPVV2)
;INTERCOMPARTMENTAL CLEARANCE
TVQ=popq
PPVQ=bsvq
IF (ABS(PPVQ) .GE. ETAMX) EXIT 1 30
Q=TVQ*EXP(PPVQ)
;PERIPHERAL VOLUME OF DISTRIBUTION
TVV3=popv3
PPVV3=bsvv3
IF (ABS(PPVV3) .GE. ETAMX) EXIT 1 40
V3=TVV3*EXP(PPVV3)
;FIRST ORDER ABSORPTION RATE CONSTANT
TVKA=SI3*ka3+SI5*ka5+SI6*ka6
PPVKA=bsvka IF (ABS(PPVKA) .GE. ETAMX) EXIT 1 50
KA=TVKA*EXP(PPVKA)
;LAG TIME
TVLAG=SI3*lag3+SI5*lag5+SI6*lag6
PPVLAG=bsvlag IF (ABS(PPVLAG) .GE. ETAMX) EXIT 1 60
ALAG1=TVLAG*EXP(PPVLAG)
;BIOAVAILABILITY (BA)
TVF1=SI3*f13+SI5*f15+SI6*f16
PPVF1=bsvf1
IF (ABS(PPVF1) .GE. ETAMX) EXIT 1 70
BA=TVF1*EXP(PPVF1)
IF (IV .GE. 1) THEN
F1=1
ELSE
F1=BA
ENDIF
;ZERO ORDER ABSORPTION DURATION
TVD2=SI1*d21+SI2*d22+SI4*d24
PPVD2=bsvd2
IF (ABS(PPVD2) .GE. ETAMX) EXIT 1 80
D2=TVD2*EXP(PPVD2)
RMIN=AMT/(60*D2) ;mcg/minute
; SCALING FOR CENTRAL COMPARTMENT (I.E., CONCENTRATION
COMPARTMENT)
S2=V2 ; DOSE IN MCG, CONCENTRATION IN NG/ML=MCG/L
$ERROR
IPRED = F
IF (MDV .EQ. 0) THEN
W = SQRT(add**2 + F*F*prop**2)
ELSE
W = 1
ENDIF
IRES=DV-IPRED
IF (W .EQ. 0) THEN
IWRES=IRES
ELSE
IWRES=IRES/W
ENDIF
Y=F+W*eps1*EXP(bsvres)
$THETA (0,11.5) ;popcl
(0,24.1) ;popv2
(0,12.9) ;popq
(0,8.22) ;popv3
(0,0.14) ;ka3
(0,0.109) ;ka5
(0,0.397) ;ka6
(0 FIX) ;lag3
(0 FIX) ;lag5
(0 FIX) ;lag6
(0,4.93) ;f13
(0,9.19) ;f15
(0,0.523) ;f16
(0,0.00072) ;d21
(0,0.00007) ;d22
(0,0.00003) ;d24
(0, 0.01) ;add
(0, 0.05) ;prop
$OMEGA 0.828 ;bsvcl
$OMEGA 1.63 ;bsvv2
$OMEGA 0 FIX ;bsvq
$OMEGA 0 FIX ;bsvv3
$OMEGA 0 FIX ;bsvka
$OMEGA 0 FIX ;bsvlag
$OMEGA 0 FIX ;bsvf1
$OMEGA 0 FIX ;bsvd2
$OMEGA 0 FIX ;bsvres
$SIGMA 1. FIX ; eps1
$ESTIMATION NOABORT MAXEVAL=9999 POSTHOC PRINT=5 SIGDIGITS=3 MSFO=
METHOD=CONDITIONAL INTERACTION
;$COV PRINT=E
$TABLE ID STDY TIME DV IPRED AMT MDV CMT CL V2 Q V3 KA ALAG1
F1 D2 RATE RMIN ETA1 ETA2 ETA3 ETA4 ETA5 ETA6 ETA7 ETA8 ETA9
IWRES IRES WT BWT AGEY AGED GAGE
NOPRINT ONEHEADER FILE=
===================================================================================
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland,
New Zealand
[EMAIL PROTECTED] <mailto:[EMAIL PROTECTED]>
tel:+64(9)373-7599x86730 fax:+64(9)373-7090
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
[EMAIL PROTECTED] tel:+64(9)373-7599x86730 fax:+64(9)373-7090
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
