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

--------------------------------------------------------

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)

--------------------------------------------------------

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

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

--------------------------------------------------------

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)

--------------------------------------------------------

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