FW: transit model

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. Best regards Dirk Garmann -------------------------------------------------------- SCHWARZ BIOSCIENCES GmbH A Member of the UCB Group Alfred-Nobel-Str. 10 - 40789 Monheim - Germany Tel +49 2173 48 0 - Fax +49 2173 48 1608 Geschaeftsfuehrer: Prof. Dr. Iris Loew-Friedrich, Detlef Thielgen Amtsgericht Duesseldorf HRB 46849 -------------------------------------------------------- Legal Notice: This electronic mail and its attachments are intended solely for the person(s) to whom they are addressed and contain information which is confidential or otherwise protected from disclosure, except for the purpose for which they are intended. Dissemination, distribution, or reproduction by anyone other than the intended recipients is prohibited and may be illegal. If you are not an intended recipient, please immediately inform the sender and return the electronic mail and its attachments and destroy any copies which may be in your possession. UCB screens electronic mails for viruses but does not warrant that this electronic mail is free of any viruses. UCB accepts no liability for any damage caused by any virus transmitted by this electronic mail. (Ref: #*BG0508)