Re: Fwd: Re: Predicting Drug in Tissue A2 using MAXEVAL=0

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