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FW: transit model

From: Garmann Dirk <Dirk.Garmann>
Date: Tue, 26 Aug 2008 18:21:40 +0200

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
 
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Received on Tue Aug 26 2008 - 12:21:40 EDT

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