lagged concentrations

From: BellyGom@aol.com Subject: [NMusers] lagged concentrations Date: 10/29/2003 2:36 PM Dear All, I have a coding problem and hope that someone can kindly enlighten me! I have a PKPD model (a zero-order one compartment model for PK: fixed), and a part of the model requires concentration estimates from different time point: $PK ~ ~ ~ S1 = V S2 = V S3 = V K = CL/V ALAG2 = THETA() ALAG3 = THETA() $DES DADT(1) = -K*A(1) DADT(2) = -K*A(2) DADT(3) = -K*A(3) C1=A(1)/S1 C2=A(2)/S2 C3=A(3)/S3 I did not initialise compartment 2 and 3 since the corresponding amount should be 0 at the beginning anyway. Note that neither comp. 2 or comp.3 is the output. Now, the above code does not work and I am not sure why... Please help! Sincerely, In-Sun Nam

From: BellyGom@aol.com Subject: Re: [NMusers] lagged concentrations Date: 10/29/2003 4:18 PM Dear Leonid, Thank you so much for your interest in the problem; hope that I will describe it a little better this time. Actually the entire control stream will be too confusing and the PD part of the corresponding PKPD model is not at all related to the problem; so I put only the PK bit (all PK parameters are fixed to the values obtained from a separate PK analysis). Basically I have a perfectly working zero-order one compartment PK model without an error. But now I need two more concentration estimates from two different time points (consequently require two more compartments): C(t) : compartment 1/V C(t-theta(1)) : compartment 2/V C(t-theta(2)) : compartment 3/V The following code should ideally had given me lagged dose amount estimates A(2), A(3); in particular A(2) should had been basically A(1), time lagged by theta(1). But unfortunately the value of A(2) stays zero regardless of time. Note that I did not initialise compartment 2 and 3 since the corresponding amount should be 0 at the beginning anyway. $PROBLEM ~~ $INPUT ID TIME DV AMDT MDV CMT ~~ $DATA ~ $SUBROUTINES ADVAN6 TOL=5 $MODEL COMP=1 COMP=2 COMP=3 $PK CALLFL=-2 CL = THETA() V = () S1 = V S2 = V S3 = V K = CL/V ALAG2 = THETA() ALAG3 = THETA() $DES DADT(1) = -K*A(1) DADT(2) = -K*A(2) DADT(3) = -K*A(3) C1=A(1)/S1 C2=A(2)/S2 C3=A(3)/S3 So help! Sincerely, In-Sun Nam

From: Leonid Gibiansky Subject: Re: [NMusers] lagged concentrations Date: 10/29/2003 4:35 PM My guess is that you did not have a dose records that assign dose to the compartments 2 and 3 (is this what you mean by "I did not initialise compartment 2 and 3"). You should put the same dose to all compartments at the same time. According to the NONMEM guide: " Absorption lag applies to the initiating dose and to all subsequent additional doses. If an absorption lag parameter is defined by PK for the dose compartment and has a positive value, then the dose ... is actually introduced into the system at a "lagged time" equal to the time at which the dose would ordinarily be introduced plus the value of the absorption lag parameter. " This gives you exactly the same profiles in each compartment, but shifted by ALAG(). Without dose, NONMEM solves equations A'=-K*A with initial condition A = 0 and gives you the perfectly correct answer A(t) = 0 Good luck Leonid

From: BellyGom@aol.com Subject: Re: [NMusers] lagged concentrations Date: 10/29/2003 4:49 PM Dear Leonid, I was really~ hopping that I can avoid duplicating doing events for additional compartments in the actual data file; it is because my full model has 4 additional compartments with lags, the data involve some 50 patients with many many doses given forever... Isn't there a more, lets say, elegant way to do the job, preferably in the control stream? Well, but then, if that is the only way, so be it! Many many thanks, In-Sun Nam

From: Leonid Gibiansky Subject: Re: [NMusers] lagged concentrations Date: 10/30/2003 10:38 AM Well, this should not be a big deal, just duplicate dosing records, nothing more. This will not increase computation time, will just add some extra rows to the data file. I do not know any more elegant way (this does not mean that there is no other way, of course) Leonid _______________________________________________________