Title: Paul R
Colleagues:
I am working with a local investigator to estimate the effects of
daily vs weekly dosing of an antibody. As such, I would like to
show the expected amounts of drug in the two tissue compartments
(A(2) and A(3)). The problem is that using MAXEVAL=0 and the same
initial estimates, I get different values for the first dose, which
should be equal for both the daily and weekly dosing. IPRED in
plasma is different for each dosing regimen, but of course PRED
gives the same end of infusion concentration. How can I code my
model so that I can report out the amount of drug in each respective
tissue compartment so that after dose 1 it is the same for the
weekly and daily dosing? ( That is, how can I code it so that A(2)
after the first weekly dose is the same as A(2) after the first of
the daily doses.)
CTL follows. Thank you!
Paul
$DATA ..\Qwk_60mg_sim.csv IGNORE=#
$SUBROUTINES ADVAN6 TOL=3
$MODEL NCOMP=3 NPAR=8
COMP=(CENTRAL DEFDOSE DEFOBS)
COMP=(TISU1)
COMP=(TISU2)
$PK
F1=1
IF(DOS1.EQ.40) F1=THETA(8)
TVCL=THETA(1)
TVV1=THETA(2)
TVQ1=THETA(3)
TVV2=THETA(4)
TVQ2=THETA(5)
TVV3=THETA(6)
CL=TVCL*EXP(ETA(1))
V1=TVV1*EXP(ETA(2))
Q1=TVQ1
V2=TVV2
Q2=TVQ2
V3=TVV3
S1=V1
K10= CL/V1
K12= Q1/V1
K21= Q1/V2
K13= Q2/V1
K31= Q2/V3
$DES
DADT(1) = -A(1)*(K10 + K13 + K12) + K21*A(2) + K31*A(3)
DADT(2) = A(1)*K12 - A(2)*K21
DADT(3) = A(1)*K13 - A(3)*K31
A2=A(2)
A3=A(3)
$ERROR
W1=THETA(7)
IPRED = LOG(0.025)
W = SQRT(W1**2)
IF(F.GT.0) IPRED = LOG(F)
IRES = IPRED-DV
IWRES = IRES/W
Y=IPRED+ W * EPS(1)
OBSV=EXP(DV)
$THETA 0.687; POPCL
$THETA 1.19 ; POPV1
$THETA 6.87; POPQ1
$THETA 1.8 ;POPV2
$THETA 0.191; POPQ2
$THETA 29.6; POPV3
$THETA 0.393; W1
$THETA 0.631; F1
$OMEGA BLOCK(2)
1.47E-01 ; IIVCL
1.87E-01 7.03E-01 ; IIVV
$SIGMA 1 FIX ; ERR_CHLO
$EST MAXEVAL=0 METHOD=COND POSTHOC NOABORT PRINT=1
$TABLE ID TIME IPRED A2 A3 NOPRINT ONEHEADER FILE=SimOut.fit
--
Paul R.
Hutson, Pharm.D.
Associate
Professor
UW School
of Pharmacy
777
Highland Avenue
Madison
WI 53705-2222
Tel 608.263.2496
Fax
608.265.5421
Pager
608.265.7000, p7856
Predicting Drug in Tissue A2 using MAXEVAL=0
Title: Paul R
Thank you, Sebastien.
Moving A2 and A3 to the $ERROR block still gives me varying values
if I use FOCE, but I presume that you mention this option for
integrated models, rather than a $DES block.
Thank you for the pointer to Alison's 02 Jun
2011 post. It explains why the first estimate for the
concentrations in the $DES block was so odd.
Can you or others explain why the FOCE method gives different drug
amounts for the different compartments with MAXEVAL=0 when the
only difference is not in the model, but in the dosing frequency?
I would expect the plots of IPRED, A2 and A3 to overlap after the
first dose of each dosing regimen, and diverge only when the
regimen with the earliest second dose finds that dose given. Why
is this so with FO, but not with FOCE?
Thank you
Paul
-------- Original Message --------
Subject:
Re: [NMusers] Predicting Drug in Tissue A2 using MAXEVAL=0
Date:
Thu, 12 Jan 2012 18:05:24 -0500
From:
Sebastien Bihorel
< [email protected] >
To:
[email protected]
Paul,
The first patient record in the output table reports very unexpected
values of any variable declared in the $DES block. This issue is
linked
to the integration process used by NONMEM and was addressed multiple
times on the list (look for Alison Boeckmann posts). This can also
affect other records when model are resest or when MTIME variables
are
used. Assuming that you don't have any dummy observation in your
dataset with CMT =2 or 3, you can still get
the amounts of drug in your 2nd and 3rd compartments at every
observation record (those defined with CMT =1) by moving the two
lines
A2 = A(2)
A3 = A(3)
from the $DES block to the $ERROR block.
As a side note, if you use NONMEM VII, you may want to add the SIGL
option in your $EST record (see section I.14 in the Introduction to
NONMEM 7 guide). There are recommended relationships between NSIG,
SIGL, and TOL when using ADVAN6, 8, 9 and 13.
Hope that helps.
Sebastien BIHOREL
Cognigen Corporation
Paul Hutson wrote:
I re-read Guide IV, III, B.14 and realized that my $EST line is
incorrect.
To compare the amount of drug in these tissue compartments with
different dosing regimens, after assigning A2=A(2) in the $DES
block, I
should NOT have used
$EST MAXEVAL=0 METHOD=COND POSTHOC NOABORT PRINT=1
Instead, this line below using the first order method and no
posthoc
worked:
$EST MAXEVAL=0 METHOD=0 NOABORT PRINT=1
Thanks.
Paul
-------- Original Message --------
Subject:
FW: [NMusers] Predicting Drug in Tissue A2 using
MAXEVAL=0
Date:
Thu, 12 Jan 2012 12:02:16 -0800
From:
Zheng, Jenny < [email protected] >
To:
[email protected]
< [email protected] >
Paul R
Hi,
Paul,
You
would expect the values are slightly different since your
output (OBSV)
included the residual errors. The IPRED should be the same
for the same
individual but different regimens.
Hope
this helps.
Jenny
Quoted reply history
From: [email protected]
[ mailto: [email protected] ]
On Behalf Of Paul Hutson
Sent: Thursday, January 12, 2012 7:29 AM
To: [email protected]
Subject: [NMusers] Predicting Drug in Tissue A2
using MAXEVAL=0
Colleagues:
I am working with a local investigator to estimate the effects
of daily
vs weekly dosing of an antibody. As such, I would like to
show the
expected amounts of drug in the two tissue compartments (A(2)
and
A(3)). The problem is that using MAXEVAL=0 and the same
initial
estimates, I get different values for the first dose, which
should be
equal for both the daily and weekly dosing. IPRED in plasma
is
different for each dosing regimen, but of course PRED gives
the same
end of infusion concentration. How can I code my model so
that I can
report out the amount of drug in each respective tissue
compartment so
that after dose 1 it is the same for the weekly and daily
dosing? (
That is, how can I code it so that A(2) after the first weekly
dose is
the same as A(2) after the first of the daily doses.)
CTL follows. Thank you!
Paul
$DATA ..\Qwk_60mg_sim.csv IGNORE=#
$SUBROUTINES ADVAN6 TOL=3
$MODEL NCOMP=3 NPAR=8
COMP=(CENTRAL DEFDOSE DEFOBS)
COMP=(TISU1)
COMP=(TISU2)
$PK
F1=1
IF(DOS1.EQ.40) F1=THETA(8)
TVCL=THETA(1)
TVV1=THETA(2)
TVQ1=THETA(3)
TVV2=THETA(4)
TVQ2=THETA(5)
TVV3=THETA(6)
CL=TVCL*EXP(ETA(1))
V1=TVV1*EXP(ETA(2))
Q1=TVQ1
V2=TVV2
Q2=TVQ2
V3=TVV3
S1=V1
K10= CL/V1
K12= Q1/V1
K21= Q1/V2
K13= Q2/V1
K31= Q2/V3
$DES
DADT(1) = -A(1)*(K10 + K13 + K12) + K21*A(2) + K31*A(3)
DADT(2) = A(1)*K12 - A(2)*K21
DADT(3) = A(1)*K13 - A(3)*K31
A2=A(2)
A3=A(3)
$ERROR
W1=THETA(7)
IPRED = LOG(0.025)
W = SQRT(W1**2)
IF(F.GT.0) IPRED = LOG(F)
IRES = IPRED-DV
IWRES = IRES/W
Y=IPRED+ W * EPS(1)
OBSV=EXP(DV)
$THETA 0.687; POPCL
$THETA 1.19 ; POPV1
$THETA 6.87; POPQ1
$THETA 1.8 ;POPV2
$THETA 0.191; POPQ2
$THETA 29.6; POPV3
$THETA 0.393; W1
$THETA 0.631; F1
$OMEGA BLOCK(2)
1.47E-01 ; IIVCL
1.87E-01 7.03E-01 ; IIVV
$SIGMA 1 FIX ; ERR_CHLO
$EST MAXEVAL=0 METHOD=COND POSTHOC NOABORT PRINT=1
$TABLE ID TIME IPRED A2 A3 NOPRINT ONEHEADER FILE=SimOut.fit
--
Paul
R.
Hutson, Pharm.D.
Associate
Professor
UW
School
of Pharmacy
777
Highland
Avenue
Madison
WI
53705-2222
Tel
608.263.2496
Fax
608.265.5421
Pager
608.265.7000,
p7856
Paul,
I am not sure what is the problem you are trying to solve. This is the estimation step, so results are conditioned on the data. Different subjects with different dosing schedules have different data; thus, you see different individual predictions. With the FO method and no POSTHOC, IPREDs are equal to PREDs: this explains the results you are seeing for FO. If you like to simulate from the model, then you need to use simulation rather than estimation step.
Results seems correct to me (and indeed, A2 and A3 should be defined in the error block): am I missing something? Is this a cross-over study with long wash out period between daily and weekly dosing regimens? Only in this case you would expect equality of the end-of-first dose predictions for each subject. Could you, please, provide the data for one subject and the output that you deem incorrect?
Thanks
Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566
Quoted reply history
On 1/13/2012 1:43 PM, Paul Hutson wrote:
> Thank you, Sebastien.
> Moving A2 and A3 to the $ERROR block still gives me varying values if I
> use FOCE, but I presume that you mention this option for integrated
> models, rather than a $DES block.
>
> Thank you for the pointer to Alison's 02 Jun 2011 post. It explains why
> the first estimate for the concentrations in the $DES block was so odd.
>
> Can you or others explain why the FOCE method gives different drug
> amounts for the different compartments with MAXEVAL=0 when the only
> difference is not in the model, but in the dosing frequency? I would
> expect the plots of IPRED, A2 and A3 to overlap after the first dose of
> each dosing regimen, and diverge only when the regimen with the earliest
> second dose finds that dose given. Why is this so with FO, but not with
> FOCE?
>
> Thank you
> Paul
>
> -------- Original Message --------
> Subject: Re: [NMusers] Predicting Drug in Tissue A2 using MAXEVAL=0
> Date: Thu, 12 Jan 2012 18:05:24 -0500
> From: Sebastien Bihorel <[email protected]>
> To: [email protected]
>
> Paul,
>
> The first patient record in the output table reports very unexpected
> values of any variable declared in the $DES block. This issue is linked
> to the integration process used by NONMEM and was addressed multiple
> times on the list (look for Alison Boeckmann posts). This can also
> affect other records when model are resest or when MTIME variables are
> used. Assuming that you don't have any dummy observation in your dataset
> with CMT =2 or 3, you can still get the amounts of drug in your 2nd and
> 3rd compartments at every observation record (those defined with CMT =1)
> by moving the two lines
> A2 = A(2)
> A3 = A(3)
> from the $DES block to the $ERROR block.
>
> As a side note, if you use NONMEM VII, you may want to add the SIGL
> option in your $EST record (see section I.14 in the Introduction to
> NONMEM 7 guide). There are recommended relationships between NSIG, SIGL,
> and TOL when using ADVAN6, 8, 9 and 13.
>
> Hope that helps.
>
> Sebastien BIHOREL
> Cognigen Corporation
>
> Paul Hutson wrote:
>
> > I re-read Guide IV, III, B.14 and realized that my $EST line is incorrect.
> > To compare the amount of drug in these tissue compartments with
> > different dosing regimens, after assigning A2=A(2) in the $DES block,
> > I should NOT have used
> >
> > $EST MAXEVAL=0 METHOD=COND POSTHOC NOABORT PRINT=1
> >
> > Instead, this line below using the first order method and no posthoc
> > worked:
> >
> > $EST MAXEVAL=0 METHOD=0 NOABORT PRINT=1
> > Thanks.
> > Paul
> >
> > -------- Original Message --------
> > Subject: FW: [NMusers] Predicting Drug in Tissue A2 using MAXEVAL=0
> > Date: Thu, 12 Jan 2012 12:02:16 -0800
> > From: Zheng, Jenny <[email protected]>
> > To: [email protected] <[email protected]>
> >
> > Hi, Paul,
> >
> > You would expect the values are slightly different since your output
> > (OBSV) included the residual errors. The IPRED should be the same for
> > the same individual but different regimens.
> >
> > Hope this helps.
> >
> > Jenny
> >
> > *From:*[email protected]
> > [mailto:[email protected]] *On Behalf Of *Paul Hutson
> > *Sent:* Thursday, January 12, 2012 7:29 AM
> > *To:* [email protected]
> > *Subject:* [NMusers] Predicting Drug in Tissue A2 using MAXEVAL=0
> >
> > Colleagues:
> > I am working with a local investigator to estimate the effects of
> > daily vs weekly dosing of an antibody. As such, I would like to show
> > the expected amounts of drug in the two tissue compartments (A(2) and
> > A(3)). The problem is that using MAXEVAL=0 and the same initial
> > estimates, I get different values for the first dose, which should be
> > equal for both the daily and weekly dosing. IPRED in plasma is
> > different for each dosing regimen, but of course PRED gives the same
> > end of infusion concentration. How can I code my model so that I can
> > report out the amount of drug in each respective tissue compartment so
> > that after dose 1 it is the same for the weekly and daily dosing? (
> > That is, how can I code it so that A(2) after the first weekly dose is
> > the same as A(2) after the first of the daily doses.)
> > CTL follows. Thank you!
> > Paul
> >
> > $DATA ..\Qwk_60mg_sim.csv IGNORE=#
> >
> > $SUBROUTINES ADVAN6 TOL=3
> > $MODEL NCOMP=3 NPAR=8
> > COMP=(CENTRAL DEFDOSE DEFOBS)
> > COMP=(TISU1)
> > COMP=(TISU2)
> >
> > $PK
> > F1=1
> > IF(DOS1.EQ.40) F1=THETA(8)
> > TVCL=THETA(1)
> > TVV1=THETA(2)
> > TVQ1=THETA(3)
> > TVV2=THETA(4)
> > TVQ2=THETA(5)
> > TVV3=THETA(6)
> >
> > CL=TVCL*EXP(ETA(1))
> > V1=TVV1*EXP(ETA(2))
> > Q1=TVQ1
> > V2=TVV2
> > Q2=TVQ2
> > V3=TVV3
> > S1=V1
> >
> > K10= CL/V1
> > K12= Q1/V1
> > K21= Q1/V2
> > K13= Q2/V1
> > K31= Q2/V3
> >
> > $DES
> > DADT(1) = -A(1)*(K10 + K13 + K12) + K21*A(2) + K31*A(3)
> > DADT(2) = A(1)*K12 - A(2)*K21
> > DADT(3) = A(1)*K13 - A(3)*K31
> > A2=A(2)
> > A3=A(3)
> >
> > $ERROR
> > W1=THETA(7)
> > IPRED = LOG(0.025)
> > W = SQRT(W1**2)
> > IF(F.GT.0) IPRED = LOG(F)
> > IRES = IPRED-DV
> > IWRES = IRES/W
> > Y=IPRED+ W * EPS(1)
> > OBSV=EXP(DV)
> >
> > $THETA 0.687; POPCL
> > $THETA 1.19 ; POPV1
> > $THETA 6.87; POPQ1
> > $THETA 1.8 ;POPV2
> > $THETA 0.191; POPQ2
> > $THETA 29.6; POPV3
> >
> > $THETA 0.393; W1
> > $THETA 0.631; F1
> >
> > $OMEGA BLOCK(2)
> > 1.47E-01 ; IIVCL
> > 1.87E-01 7.03E-01 ; IIVV
> >
> > $SIGMA 1 FIX ; ERR_CHLO
> >
> > $EST MAXEVAL=0 METHOD=COND POSTHOC NOABORT PRINT=1
> > $TABLE ID TIME IPRED A2 A3 NOPRINT ONEHEADER FILE=SimOut.fit
> >
> > --
> >
> > Paul R. Hutson, Pharm.D.
> >
> > Associate Professor
> >
> > UW School of Pharmacy
> >
> > 777 Highland Avenue
> >
> > Madison WI 53705-2222
> >
> > Tel 608.263.2496
> >
> > Fax 608.265.5421
> >
> > Pager 608.265.7000, p7856