Re: 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