Re: FW: transit model

Dear Dirk (and all), This is a tricky one. After we got our heads together to look at it, we realized that it's a bit more complex than it appears. The reason why we use greater-than or equal to (T.GE.TDOS) instead of (T.GT.TDOS) is to get around an issue with NONMEM. The easiest way to explain why is through an example - given multiple dosing every 12 hours, and observations at 1, 2, 4, and 8 h post-dose, time after dose (TAD) will need to be set to 0 at every 12-hourly dosing event - so at this point, TAD==0 and TDOS==12. However, in order to integrate between 8 h and 12 h in this scheme, NONMEM will use a TDOS value of 12 h here, resulting in negative values of TAD over the 8-12h period - which will clearly produce undesirable results. Using the IF-THEN structure with (T.GE.TDOS) is a cheat to overcome this. However, as Sebastien pointed out, another assumption is introduced by doing it this way - the dose is assumed to be fully absorbed by the last observation event, in this case 8 h (as opposed to the time of the next dose, 12 h). This may have fairly problematic consequences, especially where you have a series of dosing events without observations between them. We think the best way to tackle this will be to add dummy observation records (using EVID==2) at inter-dose troughs (e.g. 11.9 h) between each successive dose event - another method might be to leverage NONMEM VI's very helpful model event time (MTIME) variable to take care of this. Hope this was helpful! Best Justin (and Rada) Justin Wilkins Novartis Pharma AG PH346, MODELING & SIMULATION CHBS, WSJ-027.1.084 Novartis Pharma AG Lichtstrasse 35 CH-4056 Basel Switzerland Phone: +41 61 324 6549 Fax: +41 61 324 3039 Mobile: +41 76 561 0949 Email : [EMAIL PROTECTED] Sébastien Bihorel <[EMAIL PROTECTED]> Sent by: [EMAIL PROTECTED] 27/08/2008 15:59 To Garmann Dirk <[EMAIL PROTECTED]> cc [email protected] Subject Re: [NMusers] FW: transit model (Sorry for the spelling mistakes) Dirk, This absorption model can correctly accommodate multiple dosing only if the absorption of dose n is complete when dose n+1 is given ! Since the input is hard-coded and reset at each dose, you have to make sure that your estimates for MTT and NN provide this complete absorption. Otherwise, a part of each dose never enters the system. I don't really understand how you implemented the transit model but you may refer to the following code (for Wings for NONMEM) that worked just fine for me. The frame time for the input function has to start at zero, so I used a time transform based on a dosing interval of 24h. A column DAY is included in the dataset to calculate the new time MYT. Hope it helps. Sebastien Bihorel $PROBLEM Simulation Transit model $INPUT ID DOSE DAY TI24 TIME AMT RATX CMT EVID DVID DV MDV $DATA ../Data/Simulation.csv IGNORE=# $SIM (32047023) NSUB=1 $SUB ADVAN6 TOL3 $THETA (0,6.) ; POP_CL $THETA (0,100.) ; POP_V2 $THETA (0,18.) ; POP_MTT $THETA (0.00001,3.) ; POP_n $THETA (0,6.) ; POP_TABS $OMEGA BLOCK(2) 0.1 ; BSVCL 0.01 0.1 ; BSVV2 $OMEGA BLOCK(3) 0.1 ; BSVMTT 0.01 0.1 ; BSVN 0.01 0.01 0.1 ; BSVTABS $SIGMA 0.1 ;cvcp $SIGMA 0.05 ;sdcp $MODEL COMP = (ABS) ; absorption compartment COMP = (CEN) ; central compartment ;$ABBREVIATED DERIV2=NOCOMMON $PK "FIRST " COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " IMAX=1000000 IF(AMT.GT.0.AND.CMT.EQ.1)PODO=AMT; oral dose F1 = 0. F2 = 0. ECL = EXP(BSVCL) EV2 = EXP(BSVV2) EMTT = EXP(BSVMTT) ENB = EXP(BSVN) ETAB = EXP(BSVTABS) CL = POP_CL * ECL V = POP_V2 * EV2 MTT = (POP_MTT * EMTT)/60 NB = POP_n * ENB TABS = POP_TABS * ETAB KA = LOG(2)/(TABS/60) KTR = (NB+1)/MTT ; transit rate constant LNFA = 0.5*LOG(2*3.14159*NB)+NB*LOG(NB)-NB+LOG(1.+1./(12.*NB)) ; logarithmic transformation of 2nd Stirling approximation S2 = V BIO =1. $DES MYT = T -(DAY-1)*24 IF (MYT.LT.0.001) THEN INPU = 0. ELSE INPU = EXP(LOG(BIO*PODO)+LOG(KTR)+NB*LOG(KTR*MYT)-KTR*MYT-LNFA) ENDIF DADT(1) = INPU-KA*A(1) DADT(2) = (KA*A(1)-CL*A(2))/V $ERROR CP=A(2) Y=CP*(1+CVCP)+SDCP $TABLE ID DAY TIME AMT CMT EVID DVID Y CL V MTT NB TABS ECL EV2 EMTT ENB ETAB ONEHEADER NOPRINT FILE=k0ka1l.fit Garmann Dirk a écrit : Dear NONMEM users, I try to fit a dataset with a high variability in TLAG. With the standard approaches it was not possible to get successful runs (variability in Tlag is always modeled as zero, but their is clearly a high variability) Therefore I used the transit model, published by Justin Wilkins/Radoika Savic. For single dose studies it works well (improved fit/successful runs). Next , I included a multiple drug study and adapted the model. The model works, but I have some questions regarding the code (see below in red). It would be very nice if someone can help to enhance my understanding. Thank you in advance Dirk $SUBROUTINE ADVAN6 TOL=3 $MODEL NCOMP=3 COMP=(DEPOT) COMP=(CENTRAL,DEFOBS) COMP=(PERIPH) $PK "FIRST " COMMON /PRCOMG/ IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5 " IMAX=9900000 IF(AMT.GT.0.AND.CMT.EQ.1) PD=AMT IF(AMT.GT.0) TDOS=TIME TVCL=THETA(1) CL=TVCL*EXP(ETA(1)) TVV2=THETA(2) V2=TVV2*EXP(ETA(2)) TVV3=THETA(3) V3=TVV3*EXP(ETA(3)) TVQ=THETA(4) Q=TVQ*EXP(ETA(4)) ; Absorption model ;F1=0 delete NONMEMS Dose record F1=0 TVKA=THETA(5) KA=TVKA*EXP(ETA(5)) ;Mean transit time TVMTT=THETA(6) MTT=TVMTT*EXP(ETA(6)) ;Number of transit compartments TVNN=THETA(7) NN=TVNN*EXP(ETA(7)) ;Transit rate constant KTR=(NN+1)/MTT ;Sterling L=LOG(2.5066)+(NN+.5)*LOG(NN)-NN S2=V2/1000 ; DOSE : mg ; CONC: ng/ml $DES X=0.00001; Avoid LOG 0 ;multiple dose IF(T.GE.TDOS)THEN ; if current time greater than TDOS Is this correct? I think GE might be a typo and should be GT? DADT(1) = EXP(LOG(PD + X) + LOG(KTR + X)+NN*LOG(KTR*(T-TDOS)+X)-KTR*(T-TDOS)-L)-KA*A(1) ELSE ; Dose given DADT(1) = EXP(LOG(PD + X) + LOG(KTR + X)+ NN*LOG(KTR*T + X) - KTR*T - L)- KA*A(1) ENDIF T.GE.TDOS (see above) might be a typo; otherwise this equation will never be active? I try this model with GT, the fit improves, but why is this statement needed? Can someone explain this (red) part of the equation, please? I think if the time is e.g. 24 hours (time of second dose) the value of the input function will be low, as it should be to simulate the lag time (I used MTT=1, NN=4, to recalculate it). With further increased time (next doses), the value of the input function will be approximately zero (ok). But without this equation and IF(AMT.GT.0.AND.CMT.EQ.1) PD=AMT IF(AMT.GT.0) TDOS=TIME (T-TDOS) should be zero at each dose event and the value of the input function at a new dose event is also approximately zero (same as above?) Any help to enhance my understanding is welcome DADT(2)=KA*A(1)-Q/V2*A(2)+Q/V3*A(3)-CL/V2*A(2) DADT(3)=Q/V2*A(2)-Q/V3*A(3) $ERROR One last question: For some subjects I got some bizarre estimation values. I think this might be because I have sometimes dose events, but no observations (multiple dose study) prior to the next dose.. Therefore, if I correctly understand the code, the input value for these dose events will be approximately zero. Any suggestions to solve this problem are welcome. 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