From: "Vanapalli, Sreenivasa"Subject:[NMusers] Enterohepatic Circulation!!! Date:Fri, 31 May 2002 13:16:50 -0700 Hello I'm trying to model a second peak after oral administration. It looks like enterohepatic circulation. Can someone suggest me if I'm doing right? I ran the following model. But output is not showing any second peak. Is there anything I need to modify the Data file? Thanks Sreenivasa Rao Vanapalli, Ph.D. $PROBLEM $INPUT ID DOSE=AMT TIME DV CMT EVID MDV $DATA $SUBROUTINES ADVAN6 TOL=5 $MODEL NCOMPARTMENTS=6 COMP=(DEPOT, DEFDOSE) COMP=(CENTRAL, DEFOBS) COMP=(PERI) COMP=(ENT) COMP=(DUMMY1) COMP=(DUMMY2) $PK (LAGGED) CALLFL=-2 KA=THETA(1) CL=THETA(2)*EXP(ETA(1)) VC=THETA(3)*EXP(ETA(2)) VP=THETA(4) Q=THETA(5) FENT=THETA(6) ALAG5=THETA(7) ALAG6=ALAG5+THETA(8) K24=THETA(9) K42=THETA(10) K23=Q/VC K32=Q/VP KEL=CL/VC IF (NEWIND.LT.2) THEN EHYN=0 OLDTIM=0 ENDIF IF (OLDTIM.EQ.ALAG5) EHYN=1 IF (OLDTIM.EQ.ALAG6) EHYN=0 $DES DADT(1)=-KA*A(1) DADT(2)=KA*A(1)-(1-FENT)*KEL*A(2)-K23*A(2)+K32*A(3)-FENT*K24*A(2)+EHYN*K42*A (4) DADT(3)=K23*A(2)-K32*A(3) DADT(4)=FENT*K24*A(2)-EHYN*K42*A(4) DADT(5)=0 DADT(6)=0 $THETA $OMEGA $ERROR DEL=0 IF (F.EQ.0) DEL=1 W=F+DEL Y=F*(1+ERR(1))+ERR(2) IPRED=F IRES=DV-IPRED IWRES=IRES/W $SIGMA Sreenivasa Rao Vanapalli, Ph.D. Scientist, Pharmacology, Theravance Inc., South San Francisco, CA-94080 Phone: 650-808-6454 Fax : 650-808-6441 ******* From:VPIOTROV@PRDBE.jnj.com Subject:RE: [NMusers] Enterohepatic Circulation!!! Date:Mon, 3 Jun 2002 10:16:52 +0200 It seems something is missing in your control: ... IF (NEWIND.LT.2) THEN EHYN=0 OLDTIM=0 ENDIF IF (OLDTIM.EQ.ALAG5) EHYN=1 IF (OLDTIM.EQ.ALAG6) EHYN=0 ; the following is missing OLDTIM=DOSTIM ... Best regards, Vladimir ******* From:Johan.Rosenborg@astrazeneca.com Subject:RE: [NMusers] Enterohepatic Circulation!!! Date:Sun, 9 Jun 2002 10:52:54 +0200 Sreenivasa and Vladimir, I have tried to model a second peak (I suspect enterohepatic recirculation, too) after oral administration using your model Sreenivasa. It seems that the NEWIND argument and ALAG5 and ALAG6 are ignored, even with your modification Vladimir - could someone explain this part of the code? Johan Rosenborg ******* From:VPIOTROV@PRDBE.jnj.com Subject:RE: [NMusers] Enterohepatic Circulation!!! Date:Mon, 10 Jun 2002 21:51:10 +0200 Johan, The control used by Sreenivasa was proposed by Stu Beal in his Intermediate level NONMEM workshop. I recommended to Sreenivasa to include one line of code because it was in the original control. I did not test it myself. Below you will find my own control stream which may help you with your problem. It needs some tuning of course. The idea is to use 2 dummy compartments for switching EHC on and off. The data set for simulations is attached to this mail. Best regards, Vladimir $PROBLEM EHC $INPUT ID TIME AMT DV CMT $DATA nmd.txt $SUB ADVAN9 TOL=5 $MODEL COMP = (DEPOT,DEFDOSE) ; 1 COMP = (CENTRAL,DEFOBS) ; 2 COMP = (GALLBLD) ; 3 COMP = (DUMMY1) ; 4 COMP = (DUMMY2) ; 5 $PK CL = THETA(1) V = THETA(2) CLBI = THETA(3) ; CL for bile excretion KA = THETA(4) KREL = THETA(5) ; K for release from gall bladder ALAG4= THETA(6) ; Delay in release ALAG5= ALAG4 + THETA(7) ; Release stop K12 = KA K20 = CL/V K23 = CLBI/V K31 = KREL S2 = V $DES DADT(1) = -K12 * A(1) + K31 * A(4) * (1-A(5)) * A(3) DADT(2) = K12 * A(1) - K20 * A(2) - K23 * A(2) DADT(3) = K23 * A(2) - K31 * A(4) * (1-A(5)) * A(3) DADT(4) = 0 DADT(5) = 0 $ERROR Y = F*(1+ERR(1)) $THETA (0 2) ; CL (0 50) ; V (0 2) ; CLBI (0 5) ; KA (100 FIX) ; KREL (0 2) ; ALAG4 (0 .1) ; ALAG5 $OMEGA .001 $SIM (97834) $EST Data Set: 1 0 10 0 1 1 0 1 0 4 1 0 1 0 5 1 0.4 0 1 2 1 0.8 0 1 2 1 1.2 0 1 2 1 1.6 0 1 2 1 2 0 1 2 1 2.4 0 1 2 1 2.8 0 1 2 1 3.2 0 1 2 1 3.6 0 1 2 1 4 0 1 2 1 4.4 0 1 2 1 4.8 0 1 2 1 5.2 0 1 2 1 5.6 0 1 2 1 6 0 1 2 1 6.4 0 1 2 1 6.8 0 1 2 1 7.2 0 1 2 1 7.6 0 1 2 1 8 0 1 2 ******* From:Johan.Rosenborg@astrazeneca.com Subject:RE: [NMusers] Enterohepatic Circulation!!! Date:Tue, 11 Jun 2002 09:06:24 +0200 Vladimir, Thank you very much! Apparently, my problem was that I forgot to insert unit doses in the dummy compartments. I just got a similar hint via Bengt Hamrén. / Johan ******* From:VPIOTROV@PRDBE.jnj.com Subject:RE: [NMusers] Enterohepatic Circulation!!! Date:Tue, 11 Jun 2002 16:13:18 +0200 In NONMEM, especially if you deal with complicated models, the data set is in fact a part of the model. A general advice: if you have troubles first check the consistency between the control stream and the data set. Best regards, Vladimir ******* From:Luann Phillips Subject:Re: [NMusers] Enterohepatic Circulation!!! Date:Tue, 11 Jun 2002 17:58:53 -0400 The models suggested work for single dose datasets. If you need to model enterhepatic circulation for multiple dose datasets, you can use the code provided below. This code was adapted from code that Dr. Beal wrote for a model with a changing Ka value. Regards, Luann Phillips Manager of Pharmacometrics R&D Cognigen Corporation 395 Youngs Rd. Williamsville, NY 14221 (716) 633-3463 ext. 236 $PROB ENTEROHEPATIC Circulation for multiple doses - GB Empties twice following each dose ;Data Description ; Doses of Drug go into CMT=1 with ADDL=10 and II=24 ; Dummy Dose into CMT=5 with ADDL=10, II=24, and AMT=1 ; Dummy Dose into CMT=6 with ADDL=10, II=24, and AMT=1 ; Dummy Dose into CMT=7 with ADDL=10, II=24, and AMT=1 ; Dummy Dose into CMT=8 with ADDL=10, II=24, and AMT=1 ; Structural Model ; 3 compartment model plus a depot compartment ; compartment 1 serves as the depot ; compartment 2 and 3 serve as a standard 2 cmt model (central + peri.) ; compartment 4 represents the gall bladder (GB) ; To control the 'on' and 'off' of flow to the GB and from the GB to the depot a 'change point' ; modeling technique will be used. This technique uses dummy dose compartments ; to allow the estimation of lag times which will be used to control the ; on-off switch for transport to and from the GB. ; flow into the GB (K24) will be 'on' from 0 to 8 hours after each dose and ; then will be turned 'off' until the following dose ; flow from the GB to the depot compartment (K41) will be turned 'on' at ; the time of lunch and dinner(known times) and turned 'off' at an estimated time later $INPUT ID TIME AMT DV CMT EVID ADDL II $DATA $SUBROUTINES ADVAN6 TRANS1 TOL=5 $MODEL COMP=(DEPOT,DEFDOSE,INITIALOFF);dosing compartment - also used to turn on GB entry COMP=(CENTRAL,NODOSE,DEFOBS) ;central compartment COMP=(PERI,NODOSE) ;peripherial compartment COMP=(GB,NODOSE) ;gall bladder COMP=(GB4ON) ;dummy cmt to turn on GB exit at lunch COMP=(GB4OFF) ;dummy cmt to turn off GB exit at lunch COMP=(GB8ON) ;dummy cmt to turn on GB exit at dinner and turn off GB entry COMP=(GB8OFF) ;dummy cmt to turn off GB exit at dinner $PK ;this allows PK to be called at LAGGED dose times - critical CALLFL=-2 KA=THETA(1) ALAG1=THETA(2) TVCL=THETA(3) CL=TVCL*EXP(ETA(1)) TVVC=THETA(4) V2=TVVC*EXP(ETA(2)) ;flows to and from the peripherial compartment K23=THETA(5) K32=THETA(6) ;to prevent drug from accumulating in the gall bladder after the gall bladder empties ; K24 will be turned off from the last modeled time the gall bladder empties for a day ; until the next day ;K24= flow from central to the gall bladder (this will be turned on and off) ;K41= flow from gall bladder to depot (this will be turned on and off) K24=THETA(7) K41=THETA(8) ;for this model it was assumed that the amount of elapsed time the gall bladder exit rate will ; be on each time it empties will be the same (GBL) ;ALAG5 and ALAG7 were set to fixed values based upon the known time of lunch and dinner ; 0.0001 was added in each case to prevent the possibility of an infinite value of OBJ value ; because the dataset had PK samples at time=4 and time=8 ;ALAG5 AND ALAG7 could be estimated GBL=THETA(9) ALAG5=4.0001 ALAG6=ALAG5+GBL ALAG7=8.0001 ALAG8=ALAG7+GBL ;SCALE FACTOR S2=V2/1000 ;the following code sets up indicator variables to control K24 and K41 in the ; $DES block- JON/JOFF/Z control K41 and GBON/GBOFF/Z2 control K24 ;first record in an individual K24 is 'on' and K41 is 'off' IF(NEWIND.LT.2)THEN JON=0 JOFF=1 GBON=1 GBOFF=0 ENDIF ;set the values of the on'off indicator variables IF(JON.EQ.1) Z=1 IF(JOFF.EQ.1) Z=0 IF(GBON.EQ.1) Z2=1 IF(GBOFF.EQ.1) Z2=0 ;reset control switches to zero - note these do not change the value of Z or Z2 JON=0 JOFF=0 GBON=0 GBOFF=0 ;note that DOSREC(variable)=0 except at the time a dose actually enters the system ; (doses enter the system at TIME + n*II + ALAG#) ;dose records to cmt 1 should turn on GB entry (K24) IF(DOSREC(CMT).EQ.1) GBON=1 ;dose record to cmt 7 should turn off GB entry (K24) IF(DOSREC(CMT).EQ.7) GBOFF=1 ;dose records to cmt=5 and cmt=7 should turn on GB exit (K41) IF(DOSREC(CMT).EQ.5.OR.DOSREC(CMT).EQ.7) JON=1 ;dose records to cmt=6 or 8 should turn off GB exit (K41) IF(DOSREC(CMT).EQ.6.OR.DOSREC(CMT).EQ.8) JOFF=1 $DES K10=CL/V2 DADT(1) = -KA*A(1)+K41*Z*A(4) DADT(2) = KA*A(1) + K32*A(3) - K23*A(2) - K24*Z2*A(2) - K10*A(2) DADT(3) = K23*A(2) - K32*A(3) DADT(4) = K24*Z2*A(2) - K41*Z*A(4) DADT(5) = 0 DADT(6) = 0 DADT(7) = 0 DADT(8) = 0 $ERROR Y = F * (1 + EPS(1)) $THETA (0, 0.8) ;Ka :theta 1 (0, 0.3) ;lag time for depot 1 cmt:theta 2 (0,20) ;clearance:theta 3 (0,80) ;Vc:theta 4 (0,0.15) ;k23:theta 5 (0,0.09) ;k32: theta 6 (0, 0.2) ;K24:theta 7 (0, 1) ;K41:theta 8 (0, 0.5) ;elapsed time GB exit is 'on' (Theta9) $OMEGA 0.25 0.25 $SIGMA 0.04