Indirect response model in NONMEM

From: "Gordi, Toufigh" Toufigh.Gordi@cvt.com Subject: [NMusers] Indirect response model in NONMEM Date: Wed, August 25, 2004 5:04 pm Dear all, I am trying to fit an indirect response model (decrease in KIN) to some data. I have fairly good data, including pre-dose observations. There were three different dosings: oral, iv bolus and iv bolus+iv infusion. The PK part is fixed based on individual PK estimates. This is a sample of the model code: $SUBROUTINE ADVAN9 TRANS1 TOL=5 $MODEL NCOMP=5 COMP = (GUT) COMP = (CENT) COMP = (PRIPH) COMP = (PER2) COMP = (EFF) $PK CL=CL1 ... IEFF=THETA(1) IC50=THETA(2)*EXP(ETA(1)) KOUT=THETA(3) KIN=THETA(4) S2=VC D2=DUR F1=BAV $DES ... CONC=A(2)/VC HIT=IEFF*CONC/(IC50+CONC) ... DADT(5)=KIN*(1-HIT)-KOUT*A(5) Could anybody give me some guidance on how the data file should be constructed? And how the data file and the control stream should be modified in case I want to estimate a baseline value? I have found some previous comments on "initializing" the effect compartment but have not been able to make it work. Thank you! Toufigh Gordi

From:"Luann Phillips" luann.phillips@cognigencorp.com Subject: RE: [NMusers] Indirect response model in NONMEM Date: Wed, August 25, 2004 6:10 pm Toufigh, Question: Can you actually measure cmt=5? If yes: Add a record to your dataset at time=0 (very first record) with cmt=5, amt=first concentration value from cmt=5, and dv=missing. In the control stream add F5=1*exp(eta(n)) to allow for estimation of measurement error in the first concentration of cmt=5. You can keep the first concentration from cmt=5 as an observation record in addition to using it as a dose record but I usually delete it. If no: Add a record to your dataset at time=0 (very first record) with cmt=5, set amt=1. All later predictions of A(5) will be relative concentrations (ie., fractional changes) If you can not measure A(5), you will never be able to estimate a baseline value for the compartment. You assume a beginning concentration (amt=1) and then your model estimates the relative impact that the drug has on CMT=5. Note: In both cases, you should treat it as a bolus dose. If whatever A(5) represents is at steady-state prior to introducing the drug, then also use SS=1. (Review the bug about ADVAN9 and the SS6 routine). Also, make sure that IEFF is restricted between 0 and 1 to prevent your input rate for cmt=5 from becoming negative. Regards, Luann

From:"mathangi" mathangi@msn.com Subject: RE: [NMusers] Indirect response model in NONMEM Date: Wed, August 25, 2004 6:58 pm Hello Toufigh, In order to initialize the response compartment to the baseline value, you can use the following addition in the code: $PK CL=CL1 ... IEFF=THETA(1) IC50=THETA(2)*EXP(ETA(1)) KOUT=THETA(3) KIN=THETA(4) S2=VC D2=DUR F1=BAV F5=KIN/KOUT ;Baseline value And accordingly, the data file is arranged by including AMT=1 for CMT=5 at TIME=0. ID TIME AMT EFF CMT 1 0 100 0 1 1 0 1 0 5 1 0 0 14.739 5 1 0.25 0 12.633 5 1 0.5 0 10.043 5 1 0.75 0 9.5252 5 1 1 0 8.9563 5 1 1.5 0 6.5243 5 1 2 0 5.2844 5 1 2.5 0 4.6631 5 1 3 0 4.2629 5 1 4 0 3.5792 5 1 6 0 3.1123 5 1 8 0 3.275 5 Hope this helps Mathangi Gopalakrishnan _______________________________________________________