Re: lagged absorption and empirical input function

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: [email protected] [mailto:[email protected]] On > Behalf Of Tremblay, Pierre-Olivier > Sent: Wednesday, July 27, 2011 11:10 PM > To: Luann Phillips > Cc: [email protected] > 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:[email protected]] > Envoyé : 27 juillet 2011 22:01 > À : Tremblay, Pierre-Olivier > Cc : [email protected] > 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