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RE: lagged absorption and empirical input function

From: Tremblay, Pierre-Olivier <potremblay>
Date: Wed, 27 Jul 2011 23:10:06 -0400

Thank you Luann and Jan-Stefan for your suggestions. If I understand =
correctly you are suggesting I use ADVAN1 or another "pre-coded" ADVAN =
routine which precludes the use of the $DES block. In fact, I actually =
have a reasonnable fit to my data from a zero-order input (pretty sharp =
peaks) and with duration (D1) set as a fixed-effect, using either ADVAN1 =
or ADVAN5. Obviously, with these ADVANs, lag-times are a matter of =
declaring ALAGs (or sometimes using transit compartments to fit the =
model to slowly increasing early concentrations as Jan-Stefan =
suggested).

However, I deliberately choose to have an empirical p.d.f. (weibull, =
inverse gaussian or other) as an input because that will be used in a =
later IVIVC modeling and the cumulative density distribution of these =
functions can be readily fitted to dissolution data. The thing is this, =
one of the formulations I have to work with is enteric-coated, hence the =
need to model a lag-time.

My problem is that MTIME works perfectly fine with rate constants in =
differential equations but apparently not so much with "block" =
functions, so to speak. An (more probable) alternative is that the way I =
use MTIME is wrong.

From my understanding, coding discontinuous change-events with =
conditional IF statements in a $DES block may not be a very good idea. =
That's the reason I inquired about MTIME as an alternative.

 I paste below a larger chunck of my control file so you may see what I =
mean.

$SUBROUTINE ADVAN6 TOL=6
$MODEL NCOMP=1 COMP=(CENTRAL)
$PK
   CV=THETA(1)*EXP(ETA(1))
   CV2=CV**2
   MDT=THETA(2)*EXP(ETA(2))
   K=THETA(3)*EXP(ETA(3))
   V=THETA(4)*EXP(ETA(4))
   MTIME(1)=THETA(5)+ETA(5)
   DOSE=1000000
$DES
   P1=2*3.141593*CV2*(T+0.00001)**3
   P2=((T+0.00001)-MDT)**2
   P3=2*CV2*MDT*(T+0.00001)
   P4=SQRT(MDT/P1)
   RATIO=-1*(P2/P3)
   P5=EXP(RATIO)
     IG=P4*P5
       INPUT=IG*MPAST(1)
          DADT(1)=(DOSE/V)*INPUT-K*A(1)

Thanks again :o)

Pierre-Olivier

-----Message d'origine-----
De : Luann Phillips [mailto:Luann.Phillips
Envoyé : 27 juillet 2011 22:01
À : Tremblay, Pierre-Olivier
Cc : nmusers
Objet : Re: [NMusers] lagged absorption and empirical input function

Pierre-Olivier,

NONMEM takes care of all inputs via the structure of dosing records in =
the input dataset. Therefore, they are not included in the $DES block.

Instead:

In the input dataset

ID TIME AMT DV etc.
1 0 100 .
1 1 . 5
etc.


$PK
ALAG1=THETA(#) ;this will be the estimate of the absorption lag
S1=1/V
etc.

$DES
;note NONMEM codes diff. eqs. in amount units. The scale parameter (S1) =
;in $PK is used to convert the amount (AMT) unit to the DV (or conc.) =
;unit ;NONMEM will insert the dose of 100 at the TIME of the dose in the =
;dataset + ALAG1. The input will remain zero until that time =
automatically.

DADT(1)=-K*A(1)

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

If you are fitting a basic 1 cmt model with first-order elimination, I =
would recommend using subroutine ADVAN1 TRANS1. You don't provide $DES =
for this model. You just supply $PK.

$PK
K=THETA(1)
V=THETA(2)
ALAG1=THETA(3)
S1=1/V ;or whatever is appropriate for your units of dose,v,and dv.


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

Best Regards,

Luann Phillips
Director, PK/PD
Cognigen Corporation


Tremblay, Pierre-Olivier wrote:
> Hi,
>
> I'm trying to implement an absorption lag-time into a model described
> by differential equations and using an empirical input function.
>
> My initial idea was to define a MTIME(1) corresponding to the lag-time =

> and to use MPAST(1) to set the start of the input as below.
>
> DADT(1)=(DOSE/V)*INPUT*MPAST(1)-K*A(1)
>
> However, I only end up with no input at all in the system resulting in =

> simulated DV of 0 ± residual error. The issue seems related to the
> use MPAST with the input function but I don't know how.
>
> Would anyone be kind enough to point me in the right direction?
>
> Thanks,
>
> Pierre-Olivier
>
Received on Wed Jul 27 2011 - 23:10:06 EDT

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