From: "Jim Jiang"Subject: [NMusers] PD lag time in $DES Date: Wed, November 17, 2004 7:02 pm Dear All, I am using NONMEM to estimate PKPD parameters simultaneously. But the drug I am studying has indirect PD response. I would like to know how to estimate PD lag-time while using differential equation. Many Thanks Jim Dr. Jim Xuemin Jiang N415, Faculty of Pharmacy, Building A15, The University of Sydney, NSW, 2006 Telephone: 61 2 90365025 Fax: 61 2 93514391 Email: xuemin@pharm.usyd.edu.au _______________________________________________________ From: "mathangi" mathangi@msn.com Subject: RE: [NMusers] PD lag time in $DES Date: Thu, November 18, 2004 10:02 am Dr.Jiang, If I understand your question correctly, I am assuming you want to model the delay in your pharmacodynamic response using an indirect response model. If it is so, below is an example and part of the code for an iv bolus - one compartment model and inhibitory indirect response model . $SUBROUTINE ADVAN6 TRANS1 TOL=3 $MODEL COMP = CENTRAL COMP = EFFECT $PK CL = CLI ; INDIVIDUAL CLEARANCE IN L/HR V = VI ; INDIVIDUAL VOLUME OF DISTRIBUTION IN L KIN = THETA(1)*EXP(ETA(1)) ; BASAL ZERO ORDER PRODUCTION RATE OF BIOMARKER KOUT = THETA(2)*EXP(ETA(2)) ; BASAL FIRST ORDER RATE CONSTANT FOR ELIMINATION ; OF BIOMARKER IC50 = THETA(3)*EXP(ETA(3)) ;CONCENTRATION OF DRUG AT 50% OF MAXIMUM OF INHIBITION S1 = V S2 = 1 F2 = KIN/KOUT ;BASELINE RESPONSE; R0 = KIN/KOUT $DES DADT(1) = -CL/V*A(1) ;PLASMA COMPARTMENT INH = A(1)/(IC50+A(1)) ;INHIBITORY FUNCTION DADT(2) = KIN*(1-INH)-KOUT*A(2) ; INDIRECT RESPONSE MODEL I And accordingly, the data file can be arranged by including AMT=1 for CMT=2 at TIME=0 to initialise the response compartment. Please let me know, if this is what you wanted. Thanks Mathangi _______________________________________________________ From: Perez Ruixo, Juan Jose [PRDBE] JPEREZRU@PRDBE.jnj.com Subject: RE: [NMusers] PD lag time in $DES Date: Thursday, 18 November 2004 11:33 Dear Jim, You may want to have a look to a recent PAGE presentation, "NONMEM Implementation of Cell Lifespan Models for Hematological Drug Effects". http://www.page-meeting.org/page/page2004/Kimko.pdf Juan Jose Perez Ruixo, PhD. Advanced PK/PD Modelling & Simulation, Johnson & Johnson Pharmaceutical Research & Development, Beerse (Belgium). _______________________________________________________ From: mark.e.sale@gsk.com Subject: RE: [NMusers] PD lag time in $DES Date: Thu, November 18, 2004 10:46 am Jim, This isn't easy. In simulation packages, a "pipe" is created by a long series of concatenated compartments (in ACSL is was 50), as in: DADT(1) = -K*A(1) DADT(2) = K*A(1)-K*A(2) DADT(3) = K*A(2)-K*A(3) . . . DADT(50) = K*A(49)-K*A(50) 50 compartments will give a very nice "square wave" delay effect, but is numerically very difficult for estimation, even though there is only one parameter, which describes the delay. I've used a smaller number of compartments (2 or 3), but that doesn't really give a lag/delay, more of smudging sort of effect. In $PRED, you can just do LAG = THETA() the use T-LAG But, there is not, as far as I know, an (easy) way to store what the value was at (T-LAG) using $DES. Mark Sale M.D. Global Director, Research Modeling and Simulation GlaxoSmithKline 919-483-1808 Mobile 919-522-6668 _______________________________________________________ From: "Nick Holford" n.holford@auckland.ac.nz Subject: RE: [NMusers] PD lag time in $DES Date: Thu, November 25, 2004 4:20 am Mark, mark.e.sale@gsk.com wrote: > > But, there is not, as far as I know, an (easy) way to store what the value was at (T-LAG) using $DES. > The value of a response at T-LAG can be obtained by creating a model with a duplicate set of compartments. One set of compartments is used to predict the response at T and the other at T-LAG. You need to replicate the dosing history for each set of compartments. e.g. for the simple case of a one compartment disposition with first order absorption: ID TIME AMT CMT DV 1 0 100 1 . 1 0 100 3 . ... $MODEL COMP (GUT) COMP (CP) COMP (GUTLAG) COMP (CPLAG) $PK ALAG3=THETA(lag) ... $DES DGUT=A(1) DCP=A(2) ; the value of the non-lagged conc RATEIN=KA*GUT DADT(1)=-RATEIN DADT(2)=RATEIN - DCP*CL DGUTL=A(3) DCPLAG=A(4) ; the value of the lagged conc RATELG=KA*GUTL DADT(3)=-RATELG DADT(4)=RATELG - DCPLAG*CL This DE model can be easily extended to describe a turnover model (aka indirect effect) to create a lagged effect. This code gives you simultaneous access to both the current conc/effect and the lagged conc/effect in $DES. The only tricky part of this model is the need to keep track of any time varying covariates that you might be using so that you use the correct time associated value of the covariate to influence the current or lagged compartment parameters. Nick -- Nick Holford, Dept Pharmacology & Clinical Pharmacology University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand email:n.holford@auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556 http://www.health.auckland.ac.nz/pharmacology/staff/nholford/ _______________________________________________________