Dose and concentration unit differences

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: [NMusers] Dose and concentration unit differences Date: Thu, 22 Sep 2005 14:56:10 -0700 Dear all, I am a little bit puzzled by an observation I have made when running a 2-comp PK model and would appreciate comments. I have a data file, where concentrations are given in ng/ml (which is the same as mcg/L). The dose was given as mcg. I use the log-normalized data. When I use the data as is, i.e. the data file contains the dose as mcg and the concentrations as ln(mcg/L) the model doesn't run and has problem. However, if I change the units and use ng for dose and ln(ng/L) for concentrations, i.e. simply multiply both by 1000, the model runs and gives quite acceptable results. Could anybody explain this? I give a couple of lines of the data file below: The data without any manipulations: #ID DATE=DROP TIME AMT (mcg) DV (ng/mL) EVID 4 5/15/2000 10:19 400 . 1 4 5/15/2000 10:25 . 15.9 0 4 5/15/2000 10:37 . 7.66 0 4 5/15/2000 11:04 . 4.28 0 4 5/15/2000 13:45 . 1.18 0 Dose in mcg, Conc. in ln (mcg/L). #ID DATE=DROP TIME AMT (mcg) DV (ng/mL) EVID 4 5/15/2000 10:19 400 . 1 4 5/15/2000 10:25 . 2.77 0 4 5/15/2000 10:37 . 2.04 0 4 5/15/2000 11:04 . 1.45 0 4 5/15/2000 13:45 . 0.17 0 Dose in ng, Conc. in ln(ng/L) #ID DATE=DROP TIME AMT (mcg) DV (ng/mL) EVID 4 5/15/2000 10:19 400000 . 1 4 5/15/2000 10:25 . 9.67 0 4 5/15/2000 10:37 . 8.94 0 4 5/15/2000 11:04 . 8.36 0 4 5/15/2000 13:45 . 7.07 0 Toufigh Gordi

From: Leonid Gibiansky leonidg@metrumrg.com Subject: [NMusers] Dose and concentration unit differences Date: Thu, 22 Sep 2005 23:33:08 -0400 Hi Toufigh, Is it a linear model ? What exactly is the problem with the model, what type of error NONMEM returns? Have you used any cut-off for the concentration near zero (something like if(F < 0.1) F=0.1 ? Have you tried to increase precision of the computations (SIGDIG=5)? Have you tried to start failing model from the parameter values given by the converged model ? Do you have additive component of the error model? It would be easier to debug the error with the control stream. In general, there should be no difference in solutions, but some minor detail of the model may be not-scalable (or initial values are not-scalable) leading to the differences in computations. Leonid

From: Partha Nandy partha.nandy@bms.com Subject: [NMusers] Dose and concentration unit differences Date: Fri, 23 Sep 2005 13:50:19 -0400 Hi Toufigh, Did you scale the volume in order to get the concentrations in appropriate units ? At least from the data set, it does not appear that anything is wrong, however something in the control file is probably causing the problem. -Partha

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: [NMusers] Dose and concentration unit differences Date: Wed, 28 Sep 2005 14:06:48 -0700 Hi Leonid, Sorry for the delay in my response to your mail. I was out of office for a few days and also been working on this problem a little bit. I finally managed to make the model work by a simple change from ADVAN9 to ADVAN8, with identical parameter estimates, as suggested by you. The control stream: $INPUT ID DATE=DROP TIME AMT DV EVID AGE SEXF WT CLCR NMS $DATA LNPK2.csv IGNORE=# $SUBROUTINE ADVAN9 TRANS1 TOL=5 ; or ADVAN8 $MODEL NCOMP= 2 COMP = (CENT DEFDOS DEFOBS) COMP = (PRF1) $PK "FIRST " COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " IMAX=1000000000 SLP=THETA(1)*EXP(ETA(1)) CLNR=THETA(2) CL=CLNR+SLP*CLCR VC=THETA(3)*EXP(ETA(2)) CLD2=THETA(4) V2=THETA(5) S1=VC $DES DADT(1)=-A(1)*CL/VC-A(1)*CLD2/VC+A(2)*CLD2/V2 DADT(2)=A(1)*CLD2/VC-A(2)*CLD2/V2 $ERROR IPRD = F IF(IPRD.LE.0) IPRD=0.0001 IPRED=LOG(IPRD) W = SQRT(THETA(6)**2+THETA(7)**2/IPRD**2) IRES = DV-IPRED IWRES = IRES/W Y = IPRED + W * EPS(1) $THETA (0, 1) ;1 SLP $THETA (0, 5) ;2 CLNR $THETA (0, 14) ;3 VC $THETA (0, 52) ;4 CLD2 $THETA (0, 37) ;5 V2 $THETA (0, 0.1) ;6 ERROR $THETA (0 FIX) ;7 ERROR $OMEGA 0.01 ;1 IIV SLP $OMEGA 0.01 ;2 IIV VC $SIGMA 1 FIX $ESTIMATION NOABORT MAXEVAL=9999 PRINT=10 METHOD=1 INTERACTION $COVARIANCE $TABLE ID SLP VC CL NOPRINT ONEHEADER FILE=PATAB121 $TABLE ID TIME IPRED IWRES NOPRINT ONEHEADER FILE=SDTAB121 $TABLE ID SEXF NOPRINT ONEHEADER FILE=CATAB121 $TABLE ID AGE WT CLCR NOPRINT ONEHEADER FILE=COTAB121 Toufigh _______________________________________________________