Re: Transit Absorption Model in NONMEM

On Tue, Dec 10, 2013 at 1:22 PM, Nick Holford <[email protected]>wrote: > Xinting, > > You are correct. Negative simulated measurements occur when you have an > additive residual error component which is normally distributed with mean > zero. This means that half of the additive residual errors will be > negative. When the simulated prediction is similar in size to the standard > deviation of the additive error distribution then adding a negative > residual error to the non-negative prediction can make the simulated > measurement negative. This is what happens in reality when the true > concentration approaches the baseline noise of the measurement method. > > If the estimated additive residual error standard deviation is similar to > the estimated baseline noise standard deviation then it would be reasonable > to accept non-positive simulated measurements. On the other hand if the > estimated additive residual error is much larger e.g. due to model > misspecification, then it might be more sensible to use DOWHILE to reject > the non-positive simulated values. > > Best wishes, > > Nick > > On 10/12/2013 10:21 p.m., Xinting Wang wrote: > > Dear Nick, > > Thanks very much for your comment. I want to follow up with you on the > negative simulated measurements. From my experience, I also noticed that > simulation could result in negative simulated results. This usually happens > in the terminal elimination phase of the PK profile. I am just not very > familiar with the origin of these values. Is it because we have the > additive error in the model, so that some results might be negative? > > Thank you. > > > On 10 December 2013 13:38, Nick Holford <[email protected]> wrote: > >> Xinting, >> >> The use of THETA with SIGMA 1 FIX is just a matter of style. It should >> make no real difference to the results if you do it this way or with SIGMA >> to describe the residual error. Others may wish to debate that fine >> point. >> >> The DOWHILE loop with SIMEPS is used to enforce a simulation constraint >> that the simulated measured value is always positive. The NEPS is there to >> avoid getting stuck in the DOWHILE loop. >> >> I don't think I would bother with this DOWHILE loop today. It is quite >> possible to have negative measured values when you use an additive residual >> error component. I think its a more honest simulation of the residual error >> to allow negative simulated measurements. >> >> Best wishes, >> >> Nick >> >> On 10/12/2013 6:13 p.m., Xinting Wang wrote: >> >> Dear all, >> >> I have some naive questions to ask you about the implementation of >> transit absorption model in nonmem. Below is a demo code from Prof. Holford >> in which some part of it I can not understand quite well. >> >> $PROB Transit delay >> $DATA sd.csv >> $INPUT ID TIME AMT WT DV >> $SIM (20050830 NEW) NSUB=1 >> $EST MAX=9990 SIG=6 ;PRINT=1 >> METHOD=CONDITIONAL INTERACTION >> >> $THETA >> (0,3) ; pop_cl >> (1,10) ; pop_v >> (0.1,1) ; pop_ka h-1 >> (0.1,1) ; pop_mtt h >> (1,5) ; pop_nt >> $OMEGA >> 0.09 ; ppv_cl >> 0.09 ; ppv_v >> 0.09 ; ppv_ka >> 0.09 ; ppv_mtt >> >> $THETA >> (0.001,0.1) ; RUV_CV >> (0.001,1) ; RUV_SD >> $SIGMA 1 FIX ; EPS1 >> $SIGMA 1 FIX ; EPS2 >> >> $SUBR ADVAN6 TOL=3 >> $MODEL >> COMP (TRANSIT) >> COMP (CENTRAL) >> >> $PK >> IF (NEWIND.LE.1) THEN >> DOSE=0 >> TDOSE=0 >> TLAST=0 >> ENDIF >> IF (AMT.GT.0) THEN >> DOSE=AMT >> TDOSE=TIME >> ENDIF >> CL=POP_CL*EXP(PPV_CL) >> V=POP_V*EXP(PPV_V) >> KA=POP_KA*EXP(PPV_KA) >> MTT=POP_MTT*EXP(PPV_MTT) >> NT=POP_NT >> KTR=(NT+1)/MTT >> NFAC= SQRT(2*3.1415)*NT**(NT+0.5)*EXP(-NT) >> >> ;Very important! >> F1=0 >> >> $DES >> DCP=A(2)/V >> RATEIN=KA*A(1) >> GUT=DOSE*EXP(-KTR*(T-TLAST)) >> DADT(1)=GUT*KTR*(KTR*(T-TLAST))**NT/NFAC - RATEIN >> DADT(2)=RATEIN - CL*DCP >> >> >> >> >> >> >> >> >> >> >> >> >> >> *$ERRORCP=A(2)/VY=CP*(1+RUV_CV*EPS1) + RUV_SD*EPS2IF (ICALL.EQ.4) THEN >> NEPS=0 DOWHILE(Y.LE.0.AND.NEPS.LT.100) CALL SIMEPS(EPS) >> Y=CP*(1+RUV_CV*EPS1) + RUV_SD*EPS2 NEPS=NEPS+1 ENDDOENDIFTLAST=TDOSE* >> $TABLE ID TIME >> CL V KA MTT >> CP Y >> ONEHEADER NOPRINT FILE=transit.fit >> >> >> *My questions are in the $ERROR part of this code.* >> >> 1. I noticed that EPS1 and EPS2 is fixed, and the error is simulated >> using RUV_CV and RUV_SD as thetas. What is the difference if I use below >> equation: >> Y=CP*EPS1+EPS2, and let the program to estimate EPS1 and EPS2? >> >> 2. What's the purpose of SIMEPS(EPS) here? From my understanding is that >> if ICALL equals 4, then conduct a limited number of >> Y=CP*(1+RUV_CV*EPS1)+RUV_SD*EPS2. >> >> Thanks to you all for your kind support. >> >> -- >> Xinting >> >> >> -- >> Nick Holford, Professor Clinical Pharmacology >> Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A >> University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand >> office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 >> email: [email protected] http://holford.fmhs.auckland.ac.nz/ >> >> Holford NHG. Disease progression and neuroscience. Journal of >> Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 >> http://link.springer.com/article/10.1007/s10928-013-9316-2 >> Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and >> adults. J Pharm Sci. 2013: >> http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract >> Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: >> http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html >> Holford NHG. Clinical pharmacology = disease progression + drug action. >> British Journal of Clinical Pharmacology. 2013: >> http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract >> >> > > > -- > Xinting > > > -- > Nick Holford, Professor Clinical Pharmacology > Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A > University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand > office:+64(9)923-6730 mobile:NZ +64(21)46 23 53 > email: [email protected] http://holford.fmhs.auckland.ac.nz/ > > Holford NHG. Disease progression and neuroscience. Journal of > Pharmacokinetics and Pharmacodynamics. 2013;40:369-76 > http://link.springer.com/article/10.1007/s10928-013-9316-2 > Holford N, Heo Y-A, Anderson B. A pharmacokinetic standard for babies and > adults. J Pharm Sci. 2013: > http://onlinelibrary.wiley.com/doi/10.1002/jps.23574/abstract > Holford N. A time to event tutorial for pharmacometricians. CPT:PSP. 2013;2: > http://www.nature.com/psp/journal/v2/n5/full/psp201318a.html > Holford NHG. Clinical pharmacology = disease progression + drug action. > British Journal of Clinical Pharmacology. 2013: > http://onlinelibrary.wiley.com/doi/10.1111/bcp.12170/abstract > >