Title: Paul R
Dear NM Users: 4 questions for you:
I am trying to model the PK of a drug rapidly metabolized by blood (and
tissue) esterases, which not surprisingly is given IV and has a very
short (3-6 min) half life. The control stream and some data are
provided below for illustration. I am using NM6 under Wings for
NONMEM6. The drug is given IV (Compartment 1) and I am using a very low
VI volume to get it to the right atrium quickly.
The Right Atrium (COMP) is assumed to be the site of venous sampling,
only to avoid a extra compartment.
The Lungs serve as Comp 3, and are likely to be a sink for this drug.
Comp 4 is the arterial system, from which a substantial number of
samples are drawn;
Comp 5 is the Tissue compartment, which again is a likely sink, and is
presumed (for parsimony) to empty into the Rt Atrium (Comp 2)
1) When I set TOL=6, the execution of the model doesn't even begin
interating (sat for > 24 hrs)
Why does it not even start when TOL=6, but it does when I lowered it
to TOL=3?
2)Note the $MODEL statement I am forced to use by NM with my 5 DEs:
Although I only have 5 DEs and 4-5 THETAs (I've also tried setting the
volumes without identifying them as variables), when I try running the
CTL with NPARM=5, I get an immediate run abort with the error notice
(with "X" under the DADT(5))
290 NUMBER OF BASIC PK PARAMETERS EXCEEDS VALUE OF NPARAM IN $MODEL
Why is that?
3) When I set NPAR=6 (again, even though I have only 5DEs and 5
Thetas), the model runs, but ends stating that:
0MINIMIZATION SUCCESSFUL
PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED
but only the EPSs are anywhere near a possible boundary, with final
estimates of:
CLL 8.76
CLB 0.1
CLT 55.7
VB 4.5
VI 0.001
ETASD 2.236
ERRSD 456.07 454.97
3) Is this due to a 6th THETA that should have been identified and
somehow modeled or fixed?
4) Are there suggestions you can make to this physiologic model? It
would be good for the Archive, because there are not many entries for
physiologic models.
CONTROL STREAM AND DATA
$PROBLEM
;
$INPUT ID STDY TIME AMT RATE DV AGE WGT OCC GRP COMP EVID
$DATA C:\nm6\wfn6\run\peds_adults1.csv IGNORE=#
$SUBROUTINES ADVAN9 TOL=6;
; If I use ADVAN8 or 6,it immediately aborts with the Error message:
; "NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE"
; "MAXIMUM NUMBER OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000,
EXCEEDED"
$MODEL NPARAM=6 NCOMP=5 ; Note that NPARAM=5 causes the run to fail???
COMP=(VEIN DEFDOSE); DOSING COMPARTMENT (Delivers to COMPT 3
(Lungs))
COMP=RTHEART; VENOUS SAMPLING
COMP=LUNG; LUNG (May also be a tissue sink)
COMP=ARTSAMPL; Arterial system and arterial sampling site.
COMP=TISSUE; Tissue (Likely also a tissue sink)
$PK
CALLFL=-2
CO=4.5*(WGT/70)**0.75; CARDIAC OUTPUT
TCLL=(THETA(1)*(WGT/70))**0.75; CLEARANCE FROM LUNG
CLL=TCLL*EXP(ETA(1))
CLB=THETA(2)*(WGT/70)**0.75; CLEARANCE FROM BLOOD
CLT=THETA(3)*(WGT/70)**0.75; CLEARANCE FROM TISSUE
VB=THETA(4)*WGT; VOLUME OF BLOOD
VI=THETA(5); RAPID FLUX FROM IV DOSING TO RT ATRIUM
S3=VB
;THAF=0.693/K
T1=THETA(1)
T2=THETA(2)
T3=THETA(3)
T4=THETA(4)
;AUC=AMT/CL
RAT=RATE/WGT
$DES
DADT(1)=-A(1)*(CO+CLB)/VI
;RAPID FLUX OF DRUG FROM IV SITE TO RT ATRIUM
DADT(2)=A(5)*CO/VB - A(2)*CO/VB
; RT ATRIUM (Venous Sampling site)
DADT(3)=A(1)*CO/VI + A(2)*CO/VB - A(3)*(CLL + CLB + CO)/VB
;GAIN/LOSS IN LUNG COMPT (NOT MEASURED)
DADT(4)=A(3)*CO/VB - A(4)*(CO + CLB)/VB
;ARTERIAL SAMPLE SITE (MEASURED IN PEDIATRIC TRIALS)
DADT(5)=A(4)*CO/VB - A(5)*(CO + CLB + CLT)/VB
;TISSUE SITE (Not measured, ASSUMES ESTERASE SINK IN TISSUE)
$ERROR;
IPRED=F
W1=F
DEL = 0
IF(IPRED.EQ.0) DEL = 1
IRES = DV-IPRED; NEGATIVE TREND IS OVERESTIMATING DV
IWRES = IRES/(W1+DEL)
A1=A(1)
A2=A(2)
A3=A(3)
A4=A(4)
Y = F *(1+EPS(1)) + EPS(2)
$THETA (0.0001,100,1000); CLL
$THETA (0.0001,10,1000); CLB
$THETA (0.0001,50,1000); CLT
$THETA 0.07 FIX; VB
$THETA (0.000001,0.001,1); VV
$OMEGA 5; ETACLL
;$OMEGA 1.49; ETACLB
;$OMEGA 2 2; ETACLT
$SIGMA 0.5
$SIGMA .001
;$ESTIMATION METHOD=1 MAXEVAL=9999 PRINT=10
;NOABORT MSFO=PEDADLT.MSF
;$COV MATRIX=S
$TABLE ID TIME
T1 T2 T3 T4 GRP COMP RATE NOPRINT FILE=peds_adults_co3.fit
$TABLE TIME A1 A2 A3 A4
$TABLE ID CLL CLB CLT VB
NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\PATAB1
$TABLE ID STDY OCC
NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\CATAB1
$TABLE ID WGT
NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\COTAB1
$TABLE ID TIME IPRED A1 A2 A3 A4
NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\SDTAB1
$SCAT PRED VS DV UNIT
$SCAT IRES VS PRED ORD0
$SCAT IWRES VS PRED ORD0
$SCAT IRES VS TIME ORD0
$SCAT PRED VS TIME
$SCAT IWRES VS GRP ORD0
#data snippet follows
#DV UNITS: MCG/L (ng/ml),,,,,,,,,,,
#AMT = MCG,,,,,,,,,,,
#DOSING UNITS: AMT = MG, RATE = MCG/MIN,,,,,,,,,,
#ID,STUDY,TIME,AMT,RATE,DV,AGE,WGT,OCC,GRP,COMP,EVID
41001,4,0,587.5,2350,.,2.8,4.7,1,0,1,1
41001,4,0.25,8665.625,587.5,.,2.8,4.7,1,0,1,1
41001,4,5,.,.,39,2.8,4.7,1,0,4,0
41001,4,10,.,.,162,2.8,4.7,1,0,4,0
41001,4,15,.,.,234,2.8,4.7,1,0,4,0
41002,4,0,3700,14800,.,5.4,7.4,1,0,1,1
41002,4,0.25,54575,3700,.,5.4,7.4,1,0,1,1
41002,4,5,.,.,203,5.4,7.4,1,0,4,0
41002,4,10,.,.,3745,5.4,7.4,1,0,4,0
41002,4,15,.,.,4087,5.4,7.4,1,0,4,0
41003,4,0,3100,12400,.,27.5,12.4,1,0,1,1
41003,4,0.25,45725,3100,.,27.5,12.4,1,0,1,1
41003,4,5,.,.,68,27.5,12.4,1,0,4,0
41003,4,10,.,.,810,27.5,12.4,1,0,4,0
41003,4,15,.,.,888,27.5,12.4,1,0,4,0
41004,4,0,2325,9300,.,53.4,18.6,1,0,1,1
41004,4,0.25,34293.75,2325,.,53.4,18.6,1,0,1,1
41004,4,5,.,.,316,53.4,18.6,1,0,4,0
41004,4,10,.,.,291,53.4,18.6,1,0,4,0
41004,4,15,.,.,438,53.4,18.6,1,0,4,0
41005,4,0,325,1300,.,0.1,2.6,1,0,1,1
41005,4,0.25,4793.75,325,.,0.1,2.6,1,0,1,1
41005,4,5,.,.,26,0.1,2.6,1,0,4,0
41005,4,10,.,.,17,0.1,2.6,1,0,4,0
41005,4,15,.,.,79,0.1,2.6,1,0,4,0
41007,4,0,2500,10000,.,3.7,5,1,0,1,1
41007,4,0.25,36875,2500,.,3.7,5,1,0,1,1
41007,4,5,.,.,70,3.7,5,1,0,4,0
41007,4,10,.,.,1566,3.7,5,1,0,4,0
41007,4,15,.,.,2680,3.7,5,1,0,4,0
--
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
Problems with a physiologic model
Paul,
One immediate problem is S3=VB; most likely, you need S4=VB since you
observations are in compartment 4
Also, you do not have observations in A2 in the sample data set. If you do have them elsewhere, you need to define S2 as well.
Why would you use ADVAN9 (nonlinear) rather than ADVAN5 or 7 (linear systems)?
How variable are your sampling times? The data set part that you show contain just 3 data point (5, 10, 15), same for all patients. From this, you may define at most 1-compartment model (I know that this is not a simple compartment model, but still, from 3 points you are unlikely to determine 5 thetas.
Leonid
Paul Hutson wrote:
> Dear NM Users: 4 questions for you:
>
> I am trying to model the PK of a drug rapidly metabolized by blood (and tissue) esterases, which not surprisingly is given IV and has a very short (3-6 min) half life. The control stream and some data are provided below for illustration. I am using NM6 under Wings for NONMEM6. The drug is given IV (Compartment 1) and I am using a very low VI volume to get it to the right atrium quickly. The Right Atrium (COMP) is assumed to be the site of venous sampling, only to avoid a extra compartment.
>
> The Lungs serve as Comp 3, and are likely to be a sink for this drug.
>
> Comp 4 is the arterial system, from which a substantial number of samples are drawn; Comp 5 is the Tissue compartment, which again is a likely sink, and is presumed (for parsimony) to empty into the Rt Atrium (Comp 2)
>
> 1) When I set TOL=6, the execution of the model doesn't even begin interating (sat for > 24 hrs) Why does it not even start when TOL=6, but it does when I lowered it to TOL=3?
>
> 2)Note the $MODEL statement I am forced to use by NM with my 5 DEs: Although I only have 5 DEs and 4-5 THETAs (I've also tried setting the volumes without identifying them as variables), when I try running the CTL with NPARM=5, I get an immediate run abort with the error notice (with "X" under the DADT(5))
>
> 290 NUMBER OF BASIC PK PARAMETERS EXCEEDS VALUE OF NPARAM IN $MODEL
> Why is that?
>
> 3) When I set NPAR=6 (again, even though I have only 5DEs and 5 Thetas), the model runs, but ends stating that:
>
> 0MINIMIZATION SUCCESSFUL
> PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
> THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED
>
> but only the EPSs are anywhere near a possible boundary, with final estimates of:
>
> CLL 8.76
> CLB 0.1
> CLT 55.7
> VB 4.5
> VI 0.001
> ETASD 2.236
> ERRSD 456.07 454.97
>
> 3) Is this due to a 6th THETA that should have been identified and somehow modeled or fixed?
>
> 4) Are there suggestions you can make to this physiologic model? It would be good for the Archive, because there are not many entries for physiologic models.
>
> CONTROL STREAM AND DATA
> $PROBLEM
> ;
> $INPUT ID STDY TIME AMT RATE DV AGE WGT OCC GRP COMP EVID
> $DATA C:\nm6\wfn6\run\peds_adults1.csv IGNORE=#
>
> $SUBROUTINES ADVAN9 TOL=6;
> ; If I use ADVAN8 or 6,it immediately aborts with the Error message:
> ; "NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE"
>
> ; "MAXIMUM NUMBER OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000, EXCEEDED"
>
> $MODEL NPARAM=6 NCOMP=5 ; Note that NPARAM=5 causes the run to fail???
> COMP=(VEIN DEFDOSE); DOSING COMPARTMENT (Delivers to COMPT 3 (Lungs))
> COMP=RTHEART; VENOUS SAMPLING
> COMP=LUNG; LUNG (May also be a tissue sink)
>
> COMP=ARTSAMPL; Arterial system and arterial sampling site. COMP=TISSUE; Tissue (Likely also a tissue sink)
>
> $PK
> CALLFL=-2
> CO=4.5*(WGT/70)**0.75; CARDIAC OUTPUT
> TCLL=(THETA(1)*(WGT/70))**0.75; CLEARANCE FROM LUNG
> CLL=TCLL*EXP(ETA(1))
> CLB=THETA(2)*(WGT/70)**0.75; CLEARANCE FROM BLOOD
> CLT=THETA(3)*(WGT/70)**0.75; CLEARANCE FROM TISSUE
> VB=THETA(4)*WGT; VOLUME OF BLOOD
> VI=THETA(5); RAPID FLUX FROM IV DOSING TO RT ATRIUM
>
> S3=VB
>
> ;THAF=0.693/K
> T1=THETA(1)
> T2=THETA(2)
> T3=THETA(3)
> T4=THETA(4)
>
> ;AUC=AMT/CL
> RAT=RATE/WGT
>
> $DES
>
> DADT(1)=-A(1)*(CO+CLB)/VI
> ;RAPID FLUX OF DRUG FROM IV SITE TO RT ATRIUM
>
> DADT(2)=A(5)*CO/VB - A(2)*CO/VB
> ; RT ATRIUM (Venous Sampling site)
>
> DADT(3)=A(1)*CO/VI + A(2)*CO/VB - A(3)*(CLL + CLB + CO)/VB
> ;GAIN/LOSS IN LUNG COMPT (NOT MEASURED)
>
> DADT(4)=A(3)*CO/VB - A(4)*(CO + CLB)/VB
> ;ARTERIAL SAMPLE SITE (MEASURED IN PEDIATRIC TRIALS)
>
> DADT(5)=A(4)*CO/VB - A(5)*(CO + CLB + CLT)/VB
> ;TISSUE SITE (Not measured, ASSUMES ESTERASE SINK IN TISSUE)
>
> $ERROR;
>
> IPRED=F
> W1=F
> DEL = 0
> IF(IPRED.EQ.0) DEL = 1
> IRES = DV-IPRED; NEGATIVE TREND IS OVERESTIMATING DV
> IWRES = IRES/(W1+DEL)
>
> A1=A(1)
> A2=A(2)
> A3=A(3)
> A4=A(4)
>
> Y = F *(1+EPS(1)) + EPS(2)
>
> $THETA (0.0001,100,1000); CLL
> $THETA (0.0001,10,1000); CLB
> $THETA (0.0001,50,1000); CLT
> $THETA 0.07 FIX; VB
> $THETA (0.000001,0.001,1); VV
>
> $OMEGA 5; ETACLL
> ;$OMEGA 1.49; ETACLB
> ;$OMEGA 2 2; ETACLT
>
> $SIGMA 0.5
> $SIGMA .001
>
> ;$ESTIMATION METHOD=1 MAXEVAL=9999 PRINT=10
> ;NOABORT MSFO=PEDADLT.MSF
> ;$COV MATRIX=S
>
> $TABLE ID TIME
> T1 T2 T3 T4 GRP COMP RATE NOPRINT FILE=peds_adults_co3.fit
>
> $TABLE TIME A1 A2 A3 A4
>
> $TABLE ID CLL CLB CLT VB
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\PATAB1
>
> $TABLE ID STDY OCC
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\CATAB1
>
> $TABLE ID WGT
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\COTAB1
>
> $TABLE ID TIME IPRED A1 A2 A3 A4
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\SDTAB1
>
> $SCAT PRED VS DV UNIT
> $SCAT IRES VS PRED ORD0
> $SCAT IWRES VS PRED ORD0
> $SCAT IRES VS TIME ORD0
> $SCAT PRED VS TIME
> $SCAT IWRES VS GRP ORD0
>
> #data snippet follows
>
> #DV UNITS: MCG/L (ng/ml),,,,,,,,,,,
> #AMT = MCG,,,,,,,,,,,
> #DOSING UNITS: AMT = MG, RATE = MCG/MIN,,,,,,,,,,
> #ID,STUDY,TIME,AMT,RATE,DV,AGE,WGT,OCC,GRP,COMP,EVID
> 41001,4,0,587.5,2350,.,2.8,4.7,1,0,1,1
> 41001,4,0.25,8665.625,587.5,.,2.8,4.7,1,0,1,1
> 41001,4,5,.,.,39,2.8,4.7,1,0,4,0
> 41001,4,10,.,.,162,2.8,4.7,1,0,4,0
> 41001,4,15,.,.,234,2.8,4.7,1,0,4,0
> 41002,4,0,3700,14800,.,5.4,7.4,1,0,1,1
> 41002,4,0.25,54575,3700,.,5.4,7.4,1,0,1,1
> 41002,4,5,.,.,203,5.4,7.4,1,0,4,0
> 41002,4,10,.,.,3745,5.4,7.4,1,0,4,0
> 41002,4,15,.,.,4087,5.4,7.4,1,0,4,0
> 41003,4,0,3100,12400,.,27.5,12.4,1,0,1,1
> 41003,4,0.25,45725,3100,.,27.5,12.4,1,0,1,1
> 41003,4,5,.,.,68,27.5,12.4,1,0,4,0
> 41003,4,10,.,.,810,27.5,12.4,1,0,4,0
> 41003,4,15,.,.,888,27.5,12.4,1,0,4,0
> 41004,4,0,2325,9300,.,53.4,18.6,1,0,1,1
> 41004,4,0.25,34293.75,2325,.,53.4,18.6,1,0,1,1
> 41004,4,5,.,.,316,53.4,18.6,1,0,4,0
> 41004,4,10,.,.,291,53.4,18.6,1,0,4,0
> 41004,4,15,.,.,438,53.4,18.6,1,0,4,0
> 41005,4,0,325,1300,.,0.1,2.6,1,0,1,1
> 41005,4,0.25,4793.75,325,.,0.1,2.6,1,0,1,1
> 41005,4,5,.,.,26,0.1,2.6,1,0,4,0
> 41005,4,10,.,.,17,0.1,2.6,1,0,4,0
> 41005,4,15,.,.,79,0.1,2.6,1,0,4,0
> 41007,4,0,2500,10000,.,3.7,5,1,0,1,1
> 41007,4,0.25,36875,2500,.,3.7,5,1,0,1,1
> 41007,4,5,.,.,70,3.7,5,1,0,4,0
> 41007,4,10,.,.,1566,3.7,5,1,0,4,0
> 41007,4,15,.,.,2680,3.7,5,1,0,4,0
>
> --
>
> 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,
In your code for the model DEs you have your equations like this;
DADT(4)=A(3)*CO/VB - A(4)*(CO + CLB)/VB
which is rate of change of concentration with time since your input data is
the concentration not amount. In this case A4 in the error block will also be
concentration not amount.
I guess you do not need to scale it again using VB.
Hope that helps.
Manoj
Leonid Gibiansky <[EMAIL PROTECTED]> wrote:
Paul,
One immediate problem is S3=VB; most likely, you need S4=VB since you
observations are in compartment 4
Also, you do not have observations in A2 in the sample data set. If you do have
them elsewhere, you
need to define S2 as well.
Why would you use ADVAN9 (nonlinear) rather than ADVAN5 or 7 (linear systems)?
How variable are your sampling times? The data set part that you show contain
just 3 data point (5,
10, 15), same for all patients. From this, you may define at most 1-compartment
model (I know that
this is not a simple compartment model, but still, from 3 points you are
unlikely to determine 5 thetas.
Leonid
Paul Hutson wrote:
> Dear NM Users: 4 questions for you:
>
> I am trying to model the PK of a drug rapidly metabolized by blood (and
> tissue) esterases, which not surprisingly is given IV and has a very
> short (3-6 min) half life. The control stream and some data are
> provided below for illustration. I am using NM6 under Wings for
> NONMEM6. The drug is given IV (Compartment 1) and I am using a very low
> VI volume to get it to the right atrium quickly.
> The Right Atrium (COMP) is assumed to be the site of venous sampling,
> only to avoid a extra compartment.
> The Lungs serve as Comp 3, and are likely to be a sink for this drug.
> Comp 4 is the arterial system, from which a substantial number of
> samples are drawn;
> Comp 5 is the Tissue compartment, which again is a likely sink, and is
> presumed (for parsimony) to empty into the Rt Atrium (Comp 2)
>
> 1) When I set TOL=6, the execution of the model doesn't even begin
> interating (sat for > 24 hrs)
> Why does it not even start when TOL=6, but it does when I lowered it
> to TOL=3?
>
> 2)Note the $MODEL statement I am forced to use by NM with my 5 DEs:
> Although I only have 5 DEs and 4-5 THETAs (I've also tried setting the
> volumes without identifying them as variables), when I try running the
> CTL with NPARM=5, I get an immediate run abort with the error notice
> (with "X" under the DADT(5))
> 290 NUMBER OF BASIC PK PARAMETERS EXCEEDS VALUE OF NPARAM IN $MODEL
> Why is that?
>
> 3) When I set NPAR=6 (again, even though I have only 5DEs and 5 Thetas),
> the model runs, but ends stating that:
>
> 0MINIMIZATION SUCCESSFUL
> PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
> THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED
>
> but only the EPSs are anywhere near a possible boundary, with final
> estimates of:
> CLL 8.76
> CLB 0.1
> CLT 55.7
> VB 4.5
> VI 0.001
> ETASD 2.236
> ERRSD 456.07 454.97
>
> 3) Is this due to a 6th THETA that should have been identified and
> somehow modeled or fixed?
>
> 4) Are there suggestions you can make to this physiologic model? It
> would be good for the Archive, because there are not many entries for
> physiologic models.
>
> CONTROL STREAM AND DATA
> $PROBLEM
> ;
> $INPUT ID STDY TIME AMT RATE DV AGE WGT OCC GRP COMP EVID
> $DATA C:\nm6\wfn6\run\peds_adults1.csv IGNORE=#
>
> $SUBROUTINES ADVAN9 TOL=6;
> ; If I use ADVAN8 or 6,it immediately aborts with the Error message:
> ; "NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE"
> ; "MAXIMUM NUMBER OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000,
> EXCEEDED"
>
> $MODEL NPARAM=6 NCOMP=5 ; Note that NPARAM=5 causes the run to fail???
> COMP=(VEIN DEFDOSE); DOSING COMPARTMENT (Delivers to COMPT 3 (Lungs))
> COMP=RTHEART; VENOUS SAMPLING
> COMP=LUNG; LUNG (May also be a tissue sink)
> COMP=ARTSAMPL; Arterial system and arterial sampling site.
> COMP=TISSUE; Tissue (Likely also a tissue sink)
>
>
> $PK
> CALLFL=-2
> CO=4.5*(WGT/70)**0.75; CARDIAC OUTPUT
> TCLL=(THETA(1)*(WGT/70))**0.75; CLEARANCE FROM LUNG
> CLL=TCLL*EXP(ETA(1))
> CLB=THETA(2)*(WGT/70)**0.75; CLEARANCE FROM BLOOD
> CLT=THETA(3)*(WGT/70)**0.75; CLEARANCE FROM TISSUE
> VB=THETA(4)*WGT; VOLUME OF BLOOD
> VI=THETA(5); RAPID FLUX FROM IV DOSING TO RT ATRIUM
>
> S3=VB
>
> ;THAF=0.693/K
> T1=THETA(1)
> T2=THETA(2)
> T3=THETA(3)
> T4=THETA(4)
>
>
> ;AUC=AMT/CL
> RAT=RATE/WGT
>
>
>
> $DES
>
> DADT(1)=-A(1)*(CO+CLB)/VI
> ;RAPID FLUX OF DRUG FROM IV SITE TO RT ATRIUM
>
> DADT(2)=A(5)*CO/VB - A(2)*CO/VB
> ; RT ATRIUM (Venous Sampling site)
>
> DADT(3)=A(1)*CO/VI + A(2)*CO/VB - A(3)*(CLL + CLB + CO)/VB
> ;GAIN/LOSS IN LUNG COMPT (NOT MEASURED)
>
> DADT(4)=A(3)*CO/VB - A(4)*(CO + CLB)/VB
> ;ARTERIAL SAMPLE SITE (MEASURED IN PEDIATRIC TRIALS)
>
> DADT(5)=A(4)*CO/VB - A(5)*(CO + CLB + CLT)/VB
> ;TISSUE SITE (Not measured, ASSUMES ESTERASE SINK IN TISSUE)
>
>
> $ERROR;
> IPRED=F
> W1=F
> DEL = 0
> IF(IPRED.EQ.0) DEL = 1
> IRES = DV-IPRED; NEGATIVE TREND IS OVERESTIMATING DV
> IWRES = IRES/(W1+DEL)
>
> A1=A(1)
> A2=A(2)
> A3=A(3)
> A4=A(4)
>
> Y = F *(1+EPS(1)) + EPS(2)
>
>
> $THETA (0.0001,100,1000); CLL
> $THETA (0.0001,10,1000); CLB
> $THETA (0.0001,50,1000); CLT
> $THETA 0.07 FIX; VB
> $THETA (0.000001,0.001,1); VV
>
>
> $OMEGA 5; ETACLL
> ;$OMEGA 1.49; ETACLB
> ;$OMEGA 2 2; ETACLT
>
>
> $SIGMA 0.5
> $SIGMA .001
>
>
> ;$ESTIMATION METHOD=1 MAXEVAL=9999 PRINT=10
> ;NOABORT MSFO=PEDADLT.MSF
> ;$COV MATRIX=S
>
> $TABLE ID TIME
> T1 T2 T3 T4 GRP COMP RATE NOPRINT FILE=peds_adults_co3.fit
>
> $TABLE TIME A1 A2 A3 A4
>
> $TABLE ID CLL CLB CLT VB
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\PATAB1
>
> $TABLE ID STDY OCC
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\CATAB1
>
> $TABLE ID WGT
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\COTAB1
>
> $TABLE ID TIME IPRED A1 A2 A3 A4
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\SDTAB1
>
> $SCAT PRED VS DV UNIT
> $SCAT IRES VS PRED ORD0
> $SCAT IWRES VS PRED ORD0
> $SCAT IRES VS TIME ORD0
> $SCAT PRED VS TIME
> $SCAT IWRES VS GRP ORD0
>
> #data snippet follows
>
> #DV UNITS: MCG/L (ng/ml),,,,,,,,,,,
> #AMT = MCG,,,,,,,,,,,
> #DOSING UNITS: AMT = MG, RATE = MCG/MIN,,,,,,,,,,
> #ID,STUDY,TIME,AMT,RATE,DV,AGE,WGT,OCC,GRP,COMP,EVID
> 41001,4,0,587.5,2350,.,2.8,4.7,1,0,1,1
> 41001,4,0.25,8665.625,587.5,.,2.8,4.7,1,0,1,1
> 41001,4,5,.,.,39,2.8,4.7,1,0,4,0
> 41001,4,10,.,.,162,2.8,4.7,1,0,4,0
> 41001,4,15,.,.,234,2.8,4.7,1,0,4,0
> 41002,4,0,3700,14800,.,5.4,7.4,1,0,1,1
> 41002,4,0.25,54575,3700,.,5.4,7.4,1,0,1,1
> 41002,4,5,.,.,203,5.4,7.4,1,0,4,0
> 41002,4,10,.,.,3745,5.4,7.4,1,0,4,0
> 41002,4,15,.,.,4087,5.4,7.4,1,0,4,0
> 41003,4,0,3100,12400,.,27.5,12.4,1,0,1,1
> 41003,4,0.25,45725,3100,.,27.5,12.4,1,0,1,1
> 41003,4,5,.,.,68,27.5,12.4,1,0,4,0
> 41003,4,10,.,.,810,27.5,12.4,1,0,4,0
> 41003,4,15,.,.,888,27.5,12.4,1,0,4,0
> 41004,4,0,2325,9300,.,53.4,18.6,1,0,1,1
> 41004,4,0.25,34293.75,2325,.,53.4,18.6,1,0,1,1
> 41004,4,5,.,.,316,53.4,18.6,1,0,4,0
> 41004,4,10,.,.,291,53.4,18.6,1,0,4,0
> 41004,4,15,.,.,438,53.4,18.6,1,0,4,0
> 41005,4,0,325,1300,.,0.1,2.6,1,0,1,1
> 41005,4,0.25,4793.75,325,.,0.1,2.6,1,0,1,1
> 41005,4,5,.,.,26,0.1,2.6,1,0,4,0
> 41005,4,10,.,.,17,0.1,2.6,1,0,4,0
> 41005,4,15,.,.,79,0.1,2.6,1,0,4,0
> 41007,4,0,2500,10000,.,3.7,5,1,0,1,1
> 41007,4,0.25,36875,2500,.,3.7,5,1,0,1,1
> 41007,4,5,.,.,70,3.7,5,1,0,4,0
> 41007,4,10,.,.,1566,3.7,5,1,0,4,0
> 41007,4,15,.,.,2680,3.7,5,1,0,4,0
>
> --
>
> 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
>
---------------------------------
Be a PS3 game guru.
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(I am reposting this email so that it will have the appropriate subject
line for archiving.)
All the responses to Paul's email have been relevant. I would like to
remark on few of his questions (the easy ones).
The PARAM option of $MODEL describes the number of basic PK parameters,
as defined by NM-TRAN. To NM-TRAN, a basic PK parameter is a variable
that is defined in $PK and used in the $DES block. He has 6: CO, CLB,
VI, VB, CLL, CTL. The PARAM option is not needed when the $PK and $DES
blocks are present. NM-TRAN can count for itself. PARAM is only required
when you write your own code,
e.g., $SUBR ... DES=mydes
My advice is to leave it out when the $PK and $DES block are present.
Paul asks: When I set TOL=6, the execution of the model doesn't even
begin interating (sat for > 24 hrs)
Why does it not even
start when TOL=6, but it does when I lowered it to TOL=3?
I would guess that, with TOL=6, an illegal floating point number (NaN)
has been
developed somewhere in PREDPP or NONMEM, and this has cause the code to
go into an infinite loop. NONMEM is best compiled with options such that
the run stops immediately when an illegal floating point operation has
occured. As to why this problem is sensitive to the value of TOL, and
the choice of ADVAN (6,8,9): something in the model is not well
specified, so that it is very unstable and badly behaved numerically.
In general: When using $DES, it is best to do as much of the arithmetic
as possible in $PK rather than $DES. The $PK block is evaluated far less
often. (Paul's cs specifies CALLFL=-2, as often as possible - this is
not needed with a $PK block that calculates exactly same values for
every event record, assuming that WGT is constant. Better to specify
CALLFL=1, ONCE PER IR.) Either way, the $DES block is evaluated many
times
more often than the $PK block, and all those divisions in $DES are
costly of run time.
Leonid's suggestion to compute rate constants in $PK is an excellent
one. It would be a good idea even if the D.E.'s were not linear in the
compartment amounts A(i). (If the D.E.'s are non-linear in the A(i),
then some arithmetic *must* be done in the D.E.s) But since, as Leonid
points out, the D.E.s are linear, then Pual can try to use ADVAN7
(or ADVAN5 if ADVAN7 has a numerical problem.) ADVAN5 and 7 may well be
faster and more stable than ADVAN6-8-9, although I do not have a lot of
personal experience with this.
On Sun, 11 Feb 2007 19:23:41 -0600, "Paul Hutson"
<[EMAIL PROTECTED]> said:
>
> Dear NM Users: 4 questions for you:
> I am trying to model the PK of a drug rapidly metabolized by blood (and
> tissue) esterases, which not surprisingly is given IV and has a very
> short (3-6 min) half life. The control stream and some data are provided
> below for illustration. I am using NM6 under Wings for NONMEM6. The drug
> is given IV (Compartment 1) and I am using a very low VI volume to get it
> to the right atrium quickly.
> The Right Atrium (COMP) is assumed to be the site of venous sampling,
> only to avoid a extra compartment.
> The Lungs serve as Comp 3, and are likely to be a sink for this drug.
> Comp 4 is the arterial system, from which a substantial number of samples
> are drawn;
> Comp 5 is the Tissue compartment, which again is a likely sink, and is
> presumed (for parsimony) to empty into the Rt Atrium (Comp 2)
> 1) When I set TOL=6, the execution of the model doesn't even begin
> interating (sat for > 24 hrs)
> Why does it not even start when TOL=6, but it does when I lowered it to
> TOL=3?
> 2)Note the $MODEL statement I am forced to use by NM with my 5 DEs:
> Although I only have 5 DEs and 4-5 THETAs (I've also tried setting the
> volumes without identifying them as variables), when I try running the
> CTL with NPARM=5, I get an immediate run abort with the error notice
> (with "X" under the DADT(5))
> 290 NUMBER OF BASIC PK PARAMETERS EXCEEDS VALUE OF NPARAM IN $MODEL
> Why is that?
> 3) When I set NPAR=6 (again, even though I have only 5DEs and 5 Thetas),
> the model runs, but ends stating that:
> 0MINIMIZATION SUCCESSFUL
> PARAMETER ESTIMATE IS NEAR ITS BOUNDARY
> THIS MUST BE ADDRESSED BEFORE THE COVARIANCE STEP CAN BE IMPLEMENTED
> but only the EPSs are anywhere near a possible boundary, with final
> estimates of:
> CLL 8.76
> CLB 0.1
> CLT 55.7
> VB 4.5
> VI 0.001
> ETASD 2.236
> ERRSD 456.07 454.97
> 3) Is this due to a 6th THETA that should have been identified and
> somehow modeled or fixed?
> 4) Are there suggestions you can make to this physiologic model? It
> would be good for the Archive, because there are not many entries for
> physiologic models.
> CONTROL STREAM AND DATA
> $PROBLEM
> ;
> $INPUT ID STDY TIME AMT RATE DV AGE WGT OCC GRP COMP EVID
> $DATA C:\nm6\wfn6\run\peds_adults1.csv IGNORE=#
> $SUBROUTINES ADVAN9 TOL=6;
> ; If I use ADVAN8 or 6,it immediately aborts with the Error message:
> ; "NUMERICAL DIFFICULTIES WITH INTEGRATION ROUTINE"
> ; "MAXIMUM NUMBER OF EVALUATIONS OF DIFFERENTIAL EQUATIONS, 100000,
> EXCEEDED"
> $MODEL NPARAM=6 NCOMP=5 ; Note that NPARAM=5 causes the run to fail???
> COMP=(VEIN DEFDOSE); DOSING COMPARTMENT (Delivers to COMPT 3 (Lungs))
> COMP=RTHEART; VENOUS SAMPLING
> COMP=LUNG; LUNG (May also be a tissue sink)
> COMP=ARTSAMPL; Arterial system and arterial sampling site.
> COMP=TISSUE; Tissue (Likely also a tissue sink)
> $PK
> CALLFL=-2
> CO=4.5*(WGT/70)**0.75; CARDIAC OUTPUT
> TCLL=(THETA(1)*(WGT/70))**0.75; CLEARANCE FROM LUNG
> CLL=TCLL*EXP(ETA(1))
> CLB=THETA(2)*(WGT/70)**0.75; CLEARANCE FROM BLOOD
> CLT=THETA(3)*(WGT/70)**0.75; CLEARANCE FROM TISSUE
> VB=THETA(4)*WGT; VOLUME OF BLOOD
> VI=THETA(5); RAPID FLUX FROM IV DOSING TO RT ATRIUM
> S3=VB
> ;THAF=0.693/K
> T1=THETA(1)
> T2=THETA(2)
> T3=THETA(3)
> T4=THETA(4)
> ;AUC=AMT/CL
> RAT=RATE/WGT
> $DES
> DADT(1)=-A(1)*(CO+CLB)/VI
> ;RAPID FLUX OF DRUG FROM IV SITE TO RT ATRIUM
> DADT(2)=A(5)*CO/VB - A(2)*CO/VB
> ; RT ATRIUM (Venous Sampling site)
> DADT(3)=A(1)*CO/VI + A(2)*CO/VB - A(3)*(CLL + CLB + CO)/VB
> ;GAIN/LOSS IN LUNG COMPT (NOT MEASURED)
> DADT(4)=A(3)*CO/VB - A(4)*(CO + CLB)/VB
> ;ARTERIAL SAMPLE SITE (MEASURED IN PEDIATRIC TRIALS)
> DADT(5)=A(4)*CO/VB - A(5)*(CO + CLB + CLT)/VB
> ;TISSUE SITE (Not measured, ASSUMES ESTERASE SINK IN TISSUE)
>
> $ERROR;
> IPRED=F
> W1=F
> DEL = 0
> IF(IPRED.EQ.0) DEL = 1
> IRES = DV-IPRED; NEGATIVE TREND IS OVERESTIMATING DV
> IWRES = IRES/(W1+DEL)
> A1=A(1)
> A2=A(2)
> A3=A(3)
> A4=A(4)
> Y = F *(1+EPS(1)) + EPS(2)
> $THETA (0.0001,100,1000); CLL
> $THETA (0.0001,10,1000); CLB
> $THETA (0.0001,50,1000); CLT
> $THETA 0.07 FIX; VB
> $THETA (0.000001,0.001,1); VV
> $OMEGA 5; ETACLL
> ;$OMEGA 1.49; ETACLB
> ;$OMEGA 2 2; ETACLT
> $SIGMA 0.5
> $SIGMA .001
> ;$ESTIMATION METHOD=1 MAXEVAL=9999 PRINT=10
> ;NOABORT MSFO=PEDADLT.MSF
> ;$COV MATRIX=S
> $TABLE ID TIME
> T1 T2 T3 T4 GRP COMP RATE NOPRINT FILE=peds_adults_co3.fit
> $TABLE TIME A1 A2 A3 A4
> $TABLE ID CLL CLB CLT VB
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\PATAB1
> $TABLE ID STDY OCC
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\CATAB1
> $TABLE ID WGT
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\COTAB1
> $TABLE ID TIME IPRED A1 A2 A3 A4
> NOPRINT ONEHEADER FILE=c:\NONMEM\wfn\run\SDTAB1
> $SCAT PRED VS DV UNIT
> $SCAT IRES VS PRED ORD0
> $SCAT IWRES VS PRED ORD0
> $SCAT IRES VS TIME ORD0
> $SCAT PRED VS TIME
> $SCAT IWRES VS GRP ORD0
> #data snippet follows
> #DV UNITS: MCG/L (ng/ml),,,,,,,,,,,
> #AMT = MCG,,,,,,,,,,,
> #DOSING UNITS: AMT = MG, RATE = MCG/MIN,,,,,,,,,,
> #ID,STUDY,TIME,AMT,RATE,DV,AGE,WGT,OCC,GRP,COMP,EVID
> 41001,4,0,587.5,2350,.,2.8,4.7,1,0,1,1
> 41001,4,0.25,8665.625,587.5,.,2.8,4.7,1,0,1,1
> 41001,4,5,.,.,39,2.8,4.7,1,0,4,0
> 41001,4,10,.,.,162,2.8,4.7,1,0,4,0
> 41001,4,15,.,.,234,2.8,4.7,1,0,4,0
> 41002,4,0,3700,14800,.,5.4,7.4,1,0,1,1
> 41002,4,0.25,54575,3700,.,5.4,7.4,1,0,1,1
> 41002,4,5,.,.,203,5.4,7.4,1,0,4,0
> 41002,4,10,.,.,3745,5.4,7.4,1,0,4,0
> 41002,4,15,.,.,4087,5.4,7.4,1,0,4,0
> 41003,4,0,3100,12400,.,27.5,12.4,1,0,1,1
> 41003,4,0.25,45725,3100,.,27.5,12.4,1,0,1,1
> 41003,4,5,.,.,68,27.5,12.4,1,0,4,0
> 41003,4,10,.,.,810,27.5,12.4,1,0,4,0
> 41003,4,15,.,.,888,27.5,12.4,1,0,4,0
> 41004,4,0,2325,9300,.,53.4,18.6,1,0,1,1
> 41004,4,0.25,34293.75,2325,.,53.4,18.6,1,0,1,1
> 41004,4,5,.,.,316,53.4,18.6,1,0,4,0
> 41004,4,10,.,.,291,53.4,18.6,1,0,4,0
> 41004,4,15,.,.,438,53.4,18.6,1,0,4,0
> 41005,4,0,325,1300,.,0.1,2.6,1,0,1,1
> 41005,4,0.25,4793.75,325,.,0.1,2.6,1,0,1,1
> 41005,4,5,.,.,26,0.1,2.6,1,0,4,0
> 41005,4,10,.,.,17,0.1,2.6,1,0,4,0
> 41005,4,15,.,.,79,0.1,2.6,1,0,4,0
> 41007,4,0,2500,10000,.,3.7,5,1,0,1,1
> 41007,4,0.25,36875,2500,.,3.7,5,1,0,1,1
> 41007,4,5,.,.,70,3.7,5,1,0,4,0
> 41007,4,10,.,.,1566,3.7,5,1,0,4,0
> 41007,4,15,.,.,2680,3.7,5,1,0,4,0
>
> --
>
> 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
--
Alison Boeckmann
[EMAIL PROTECTED]