Problem with predicted values for peripherial compartment

Dear Users, After a succesful estimation of PK data by using ADVAN6 I try to get some more detailed predictions for the central and peripherial compartment as well. Therefore some "blank" records were inserted to the initial data file, like this: ID AMT EVID TIME DV UVOL CMT MDV 1 4e+06 1 0.0 . 0 1 1 1 0e+00 0 0.0 0.00000 0 2 0 1 0e+00 0 0.0 0.00000 0 4 0 1 0e+00 2 0.0 . 0 2 1 1 0e+00 2 0.0 0.00000 0 3 0 1 0e+00 2 0.0 . 0 4 1 1 0e+00 0 0.5 13.93836 0 2 0 1 0e+00 0 0.5 44.12349 0 4 0 1 0e+00 0 1.0 15.06895 0 2 0 1 0e+00 0 1.0 101.76711 0 4 0 1 0e+00 2 1.0 . 0 2 1 1 0e+00 2 1.0 . 0 4 1 1 0e+00 0 2.0 13.14943 0 2 0 1 0e+00 0 2.0 108.56616 0 4 0 1 0e+00 2 2.0 . 0 2 1 1 0e+00 2 2.0 . 0 4 1 1 0e+00 2 3.0 . 0 2 1 1 0e+00 2 3.0 . 0 4 1 1 0e+00 0 4.0 10.92107 0 2 0 1 0e+00 0 4.0 117.83321 0 4 0 CMT=2 is the central CMT=4 is a peripherial comparment. The predictions for the central compartment were OK, but the predictions for peripherial compartment were identical with the central. On the top of this, there were no errors with those records where the DV was a measured value. Is there any idea? Thanks, István The model: $PROBLEM $INPUT C ID AMT EVID TIME DV UVOL CMT $DATA DATANONMEM.CSV IGNORE=C $SUBROUTINE ADVAN6 TRANS1 TOL=4 $MODEL NCOMP=4 COMP=(DEPOT,DEFDOS) COMP=(CENTRAL,DEFOBS) COMP=(URINE) COMP=(PERIPH) $PK TVKA=THETA(1) TVCL=THETA(2) TVCLR=THETA(3) TVV2=THETA(4) TVKCS=THETA(5) TVKSC=THETA(6) TVV4=THETA(7) KA=TVKA*EXP(ETA(1)) CL=TVCL*EXP(ETA(2)) CLR=TVCLR*EXP(ETA(3)) V2=TVV2*EXP(ETA(4)) KCS=TVKCS*EXP(ETA(5)) KSC=TVKSC*EXP(ETA(6)) V4=TVV4*EXP(ETA(7)) S2=V2 S3=UVOL S4=V4 $DES DADT(1)=-KA*A(1) DADT(2)= KSC*A(4)+KA*A(1)-A(2)*(CLR+CL+KCS) DADT(3)= CLR*A(2) DADT(4)= KCS*A(2)-KSC*A(4) $THETA (0,0.1) (0,0.1) (0,0.1) (0,160) (0,0.1) (0,0.1) (0,10) $OMEGA .1 .1 .1 .1 .1 .1 .1 $SIGMA 0.1 10 $ERROR IPRE=F Y=IPRE*(1+ERR(1))+ERR(2) $ESTIMATION PRINT=5 METHOD=1 POSTHOC $TABLE C ID TIME CMT EVID DV IPRE NOPRINT ONEHEADER FILE=benzopred.tab István Németh PhD Biostatistician Developmental Drug Metabolism & Pharmacokinetics Pharmacological and Drug Safety Research Gedeon Richter Plc Tel: 00 36 1 505 7082 Fax: 00 36 1 889 8526

Dear István, I think one of the problem is that you have defined compartment 2 as the default observations compartment “COMP=(CENTRAL,DEFOBS)”. If you use the CMT column it is best to not use either “DEFOBS” or “DEFDOSE”. Furthermore I do not completely understand your model. I have a few questions/comments: 1) In the dataset it looks as if you have observations from the peripheral compartment (CMT 4). How is this possible? 2) The way that you have parameterized your model it is not clearances that you are estimating (more like first order rate constants, but with one redundant parameter). Below these bullets is an example of how I would change the code. 3) From my understanding you have three very different kinds of dependent variable (plasma concentration, urine collection and “peripheral concentration”). Even so you assume the same type of residual error for all of them? I would strongly suggest that you estimate independent residual error models for the different DVs (also see example below). (It might be useful to also look into using the L2 data item but that is secondary to this comment.) 4) The kind of model that you are using does not need to use a differential equation solver (ADVAN6). It can be estimated with ADVAN5 (or ADVAN7). The way that I have coded the example below you only need to remove the $DES section and change the $SUBROUTINE statement if you want to switch to this faster method. $PROBLEM $INPUT C ID AMT EVID TIME DV UVOL CMT $DATA DATANONMEM.CSV IGNORE=C $SUBROUTINE ADVAN6 TRANS1 TOL=4 $MODEL NCOMP=4 COMP=(DEPOT) COMP=(CENTRAL) COMP=(URINE) COMP=(PERIPH) $PK TVKA = THETA(1) TVCL = THETA(2) TVCLR = THETA(3) TVV2 = THETA(4) TVQ = THETA(5) TVV4 = THETA(6) KA = TVKA*EXP(ETA(1)) CL = TVCL*EXP(ETA(2)) ; Non-renal clearance CLR = TVCLR*EXP(ETA(3)) ; Renal clearance V2 = TVV2*EXP(ETA(4)) ; Central distribution volume Q = TVKCS*EXP(ETA(5)) ; Inter-compartmental clearance V4 = TVV4*EXP(ETA(6)) ; Peripheral distribution volume K1T2 = KA K2T0 = CL/V2 K2T3 = CLR/V2 K2T4 = Q/V2 K4T2 = Q/V4 $DES DADT(1)=-K1T2*A(1) DADT(2)= K4T2*A(4) +K1T2*A(1) -(K2T3+K2T0+K2T4)*A(2) DADT(3)= K2T3*A(2) DADT(4)= K2T4*A(2) -K4T2*A(4) $THETA (0,1) (0,20) (0,20) (0,160) (0,10) (0,100) $OMEGA .1 .1 .1 .1 .1 .1 $SIGMA 0.1 10 0.1 10 0.1 10 $ERROR CP = A(2)/V2 ; Plasma concentration CU = A(3)/UVOL ; Urine concentration OC4 = A(4)/V4 ; “Peripheral concentration?” IPRE = CP ; Individual prediction of plasma conc. Y = IPRE*(1+ERR(1))+ERR(2) IF(CMT.EQ.3) THEN ; For urine collection DV IPRE = CU Y = IPRE*(1+ERR(3))+ERR(4) ENDIF IF(CMT.EQ.4) THEN ; For “Peripheral concentration?” DV IPRE = OC4 Y = IPRE*(1+ERR(5))+ERR(6) ENDIF $ESTIMATION PRINT=5 METHOD=1 POSTHOC $TABLE C ID TIME CMT EVID DV IPRE NOPRINT ONEHEADER FILE=benzopred.tab Kind regards, Martin Bergstrand, MSc, PhD student ----------------------------------------------- Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University ----------------------------------------------- <mailto:[email protected]> [email protected]

Hi Istvan, The issue is that compartment 2 is your default observation (DEFOBS) compartment. In your $ERROR block, you need something like IF (CMT.EQ.2) IPRE=A(2)/V2 IF (CMT.EQ.4) IPRE=A(4)/V4 Y=IPRE*(1+ERR(1))+ERR(2) Note that this will assume the same error structure between the two compartments which is probably not your intention. Thanks, Bill

Hi István, I am just curios to know how much, and what type, of data you have that enables you to estimate 16 parameters: 7 THETAs, 7 ETAs, and 2 ERRs. Toufigh Toufigh Gordi, PhD President, PK/PD and Clinical Pharmacology Services Rosa & Co. LLC: www.rosaandco.com E-mail: [email protected] Tel.: 408-480-7314 Fax: 408-370-9810 The information contained in this e-mail message, e-mail message sequence, and/or any enclosures is confidential, and it may be privileged and protected from unauthorized use and/or disclosure. If you are not the intended recipient, any use, dissemination, distribution, or copying is strictly prohibited. If you received this e-mail in error, PLEASE NOTIFY THE SENDER immediately and destroy this message, any enclosures, and any copies of the message and/or the enclosures. Thank you.

The CMT data item works differently with DOSE and OTHER event records (EVID=1 and 2) than it does with Observation event records (EVID=0). You need to use the PCMT data item with EVID=2. Look for PCMT in the help or html directories.