From: Ekaterina Gibiansky <*EGibiansky*>

Date: Thu, 28 Jul 2011 12:27:43 -0400

Dear Xiao,

This is not correct. When you specify ALAG1, the delay will be applied to doses

specified on the dosing records of the data file (i.e where AMT > 0), but not in

the case of Pierre-Olivier's problem where input is explicitly defined in the

control stream.

Regards,

Katya

Ekaterina Gibiansky, Ph.D.

CEO&CSO, QuantPharm LLC

Web: www.quantpharm.com

Email: EGibiansky at quantpharm.com

On 7/28/2011 11:39 AM, Xiao Hu wrote:

*> Dear Pierre-Olivier,
*

*> I think once you defined ALAG(1)=THETA() (as Luann suggested), the system will delay your input. You don't have to specify anything in the $DES block. It's worth trying.
*

*>
*

*> $PK
*

*> ALAG(1)=THETA()
*

*>
*

*> $DES
*

*> DADT(1)=(DOSE/V)*INPUT-K*A(1)
*

*>
*

*> Best regards,
*

*> Xiao (Shelley)
*

*>
*

*> -----Original Message-----
*

*> From: owner-nmusers *

*> Sent: Wednesday, July 27, 2011 11:10 PM
*

*> To: Luann Phillips
*

*> Cc: nmusers *

*> Subject: RE: [NMusers] lagged absorption and empirical input function
*

*>
*

*> 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 Thu Jul 28 2011 - 12:27:43 EDT

Date: Thu, 28 Jul 2011 12:27:43 -0400

Dear Xiao,

This is not correct. When you specify ALAG1, the delay will be applied to doses

specified on the dosing records of the data file (i.e where AMT > 0), but not in

the case of Pierre-Olivier's problem where input is explicitly defined in the

control stream.

Regards,

Katya

Ekaterina Gibiansky, Ph.D.

CEO&CSO, QuantPharm LLC

Web: www.quantpharm.com

Email: EGibiansky at quantpharm.com

On 7/28/2011 11:39 AM, Xiao Hu wrote:

Received on Thu Jul 28 2011 - 12:27:43 EDT