From: SÃ©bastien Bihorel <*sbihorel*>

Date: Wed, 27 Aug 2008 09:13:54 -0400

Dirk,

This absorption 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

the estimate you get for MTT and NN provide this complete absorption.

Otherwise, part of each dose does never enter 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 for the input function has to start at zero to 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.*
*

*>
*

*> **
*

*>
*

*> *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
*

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*

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*

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*

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*

*> information which is confidential or otherwise protected from
*

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*

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*

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*

*> ------------------------------------------------------------------------
*

Received on Wed Aug 27 2008 - 09:13:54 EDT

Date: Wed, 27 Aug 2008 09:13:54 -0400

Dirk,

This absorption 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

the estimate you get for MTT and NN provide this complete absorption.

Otherwise, part of each dose does never enter 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 for the input function has to start at zero to 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 :

Received on Wed Aug 27 2008 - 09:13:54 EDT