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
