PK/PD problem using ADVAN6

From: Kakkar, Tarundeep [mailto:tarundeep.kakkar@spcorp.com] Subject: PK/PD problem using ADVAN6 Date: Friday, March 01, 2002 8:09 AM Hi, I sent a question to nmusers. Someone suggested that the model needs ERR(1) rather than ETA(1) for the $OMEGA for the single subject and I should go with population modeling straightaway. I went and did that, but I'm not getting satisfactory results, the model converges but the fit isn't correct. The PD measurements should start coming back at later time-points according to the observed data, but in the fit the PD keeps on going down. So, I'm forwarding the email I sent to the nmusers group. Is there something wrong the way I coded the data file? Does it need a fictitious compartment (CMT = 2). Does having AMT =1 at the 0 hr value for CMT=3 somehow messes it up? I hope you can help me. Tarun I am trying to fit an Indirect response model to a drug given orally once a week. There are no PK measurements. I have a baseline value for each subject and PD measurements every week for 28 days (0, 7, 14, 21 and 28 days). I'm trying to troubleshoot this with one subject before I go to fitting all subjects and am having problems with the model converging. I don't know if the data file is setup incorrectly or if the model is incorrect or both. Is it overparameterized (4 estimates and only 5 observed values)? If it's overparametrized, how do I force it to not estimate ETA(1)? I was able to get a decent fit for this in WinNonlin. I would really appreciate if someone could help me with this. Thanks Tarun The model I wrote goes something like this (Time in hours): $PROB POP PK/PD Model $DES $INPUT ID VOL TIME DV AMT CMT $DATA data.csv IGNORE=C $SUBROUTINE ADVAN6 TRANS=1 TOL=3 $MODEL NCOMP=3 COMP=(GUT) COMP=(CENTRAL) COMP=(EFFECT) $PK KA=0.042 KE=0.022 V2=VOL S2=V2 IC50=THETA(1);*EXP(ETA(1)) KOUT=THETA(2);*EXP(ETA(3)) KIN=THETA(3);*EXP(ETA(2)) F3=KIN/KOUT $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-KE*A(2) CE=A(2)/V2 DRUG1=1-CE/(CE+IC50) DADT(3)=KIN*DRUG1-KOUT*A(3) $ERROR Y=F+ETA(1) IPRED=F and so on .... Data file: CID VOL TIME DV AMT CMT 1 91.825 0 . 3000000 1 1 91.825 0 . 1 3 1 91.825 0 43916 . 3 1 91.825 168 . 3000000 1 1 91.825 168 16638 . 3 1 91.825 336 . 3000000 1 1 91.825 336 3349 . 3 1 91.825 504 . 3000000 1 1 91.825 504 6183 . 3 1 91.825 672 . 3000000 1 1 91.825 672 5707 . 3 *************************************************************** This message and any attachments is solely for the intended recipient. If you are not the intended recipient, disclosure, copying, use, or distribution of the information included in this message is prohibited -- please immediately and permanently delete this message.

From:"Bachman, William" Subject:[NMusers] PK/PD problem using ADVAN6 [GM000245] Date:Fri, March 1, 2002 4:58 pm Tarun, I got a reasonable fit to your data for one individual with minor modifications to your control stream and data file. the data file: The dose to cmt 3 constitutes setting the initial condition in cmt 3. As such, instead of "1" it should be a number reflecting the steady state effect in the absence of drug, KIN/KOUT. You may use the observed effect at time zero if that's all you have (or an average baseline value prior to dosing). I used the observed effect at time zero here for the "dose" to cmt 3. Alternatively, model KIN as a steady state infusion, R3 (see Manual VIII, Exogenous Supplementation Example, p. 312). (I also modified the data (added a leading comma) to be compatible with PDx-Pop (and still fully NONMEM compatible)). C,Data Desc: tarun,,,,, C,ID,VOL,TIME,DV,AMT,CMT ,1,91.825,0,.,3000000,1 ,1,91.825,0,.,43916,3 ,1,91.825,0,43916,.,3 ,1,91.825,168,.,3000000,1 ,1,91.825,168,16638,.,3 ,1,91.825,336,.,3000000,1 ,1,91.825,336,3349,.,3 ,1,91.825,504,.,3000000,1 ,1,91.825,504,6183,.,3 ,1,91.825,672,.,3000000,1 ,1,91.825,672,5707,.,3 the control stream: You do need to use ERR(1) for an individual. I assume that you will input each individuals PK parameters via the data file when you move to the population model (unless there is VERY LITTLE PK variability). The "F3" statement was not needed. (There is a value in starting with an individual model, it starts off simple and you can simulate the individual to see if your initial estimates are in the ballpark. In fact, I would simulate full profiles to assure you are getting the "shape" you anticipate, your data are all trough measurements.) $PROB POP PK/PD Model $DES $INPUT C ID VOL TIME DV AMT CMT $DATA mydata.csv IGNORE=C $SUBROUTINE ADVAN8 TRANS=1 TOL=3 $MODEL NCOMP=3 COMP=(GUT) COMP=(CENTRAL) COMP=(EFFECT) $PK KA=0.042 KE=0.022 V2=VOL S2=V2 IC50=THETA(1);*EXP(ETA(1)) KOUT=THETA(2);*EXP(ETA(3)) KIN =THETA(3);*EXP(ETA(2)) ;F3=KIN/KOUT $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-KE*A(2) CE=A(2)/V2 DRUG1=1-CE/(CE+IC50) DADT(3)=KIN*DRUG1-KOUT*A(3) $THETA (0, 497) ;IC50 (0, 0.008) ;KOUT (0, 353) ;KIN $OMEGA 0.4 $ERROR Y=F+ERR(1) IPRED=F $EST MAXEVAL=1000 PRINT=5 $TABLE ID TIME CMT FILE=T2.TAB

From:"Sam Liao" Subject:RE: [NMusers] PK/PD problem using ADVAN6 [GM000245] Date:Fri, March 1, 2002 6:24 pm Hi Bill: I think the original approach Tarun used is fine too. The baseline observation also subject to measurement error. This issue has been discussed previously. ================================== File Name:99oct052000.html Subject: PD initialization Posting: October 5, 2000 12 occurence(s) of the search term liao Subject: RE: PD initialization Date: Fri, 6 Oct 2000 09:43:37 -0400 Atul: I agree with Vladimir, the AMT for CMT=2 dosing event record should be 1. I would also suggest to use $SIMULATION to verify this. Sam ============================ liao & liao Consultants, Inc 270 Kerry Lane Blue Bell, PA 19422 215-6541151 fax 2156540922 shliao@aol.com ***** From: "Bachman, William" Subject: RE: PD initialization Date: Fri, 6 Oct 2000 09 ====================================== Best regards, Sam Liao, Ph.D. PharMax Research 270 Kerry Lane, Blue Bell, PA 19422 phone: 215-6541151 efax: 1-720-2946783