Re: EHC modelling

Dear Joan I am not sure how big a gall bladder it would be if it took several hours to empty. To answer your questions: 1. I think it should work for multiple dosing 2. About MTIME, since you put FLAG=MPAST(1)-MPAST(2), this means that FLAG is 1 only between MTIME(1) and MTIME(2), since MPAST(x) is zero until MTIME(x) where after MPAST(x) is 1. So between these times is when you want metabolite to enter your central compartment since FLAG will be equal to 1. Since the gall bladder empties somewhat instantaneously after ingestion of a meal, in the code MTIME(2)= MTIME(1)+THETA(15), I would fix THETA(15) to be a few minutes (10-20), and then fix a very high rate constant (e.g. 15 or so) for metabolite transfer from the gall bladder back into the metabolite compartment (central) so that everything is emptied in a short space of time. I do not know what would be better for a metabolite between the GB compt emptying into the metabolite compt, or into the absorption compt, but the code that follows is for emptying into the metabolite compt (which is not what happens in reality). Since I do not know which of the 2 metabolites undergoes EHC, let's assume it is metabolite 1 in compartment 4. I would rewrite your code for COMPT 2 as: DADT(2)=KA*A(1)-FM1*(CL/V2)*A(2)-(1-FM1)*(CL/V2)*A(2)+K32*A(3)-K23*A(2) and for the metabolite compt as: DADT(4)=FM*(CL/V2)*A(2)-K40*A(4)-K46*A(4)+ K64*FLAG. and code your gall bladder compt 6 as: DADT(6)=K46*A(4)-K64*A(6)*FLAG. In my experience, putting MTDIFF=1 made no difference. I have limited experience with EHC myself, so that's my 2 cents worth of advice. Emmanuel Emmanuel Chigutsa (BPharm. Hons) Research Fellow, Pharmacometrics Group Division of Clinical Pharmacology, University of Cape Town K-45 Old Main Building, Groote Schuur Hospital Anzio Road, Observatory, 7925 Cape Town, South Africa Telephone: +27 214066758 Fax: +27 214066759 Mobile: +27 782826538 Email: [email protected] >>> joan hern <[email protected]> 27/01/2010 13:26 >>> Dear all, I have a parent compound and two conjugated metabolites, one of them it is supposed to show enterohepatic circulation between 6 and 10 hours post-oral administration , so now I am trying to model it using with MTIME in $Pk code (NONMEM VI). The code of my model is as follows: $PROBLEM $INPUT ID TIME AMT CMT OCC DV MDV GRP EVID ADDL II $DATA data.prn IGNORE=# $SUBROUTINES ADVAN6 TOL=3 $MODEL COMP=(DEPOT) COMP=(CENTRAL) COMP=(PERIPH1) COMP=(CMET1) COMP=(CMET2) COMP=(GALLB) $PK ;--------------Absorption parameters------------------- F1 = 1 KA = THETA(1) ;--------------Disposition parameters------------------- V2 = THETA(2)*EXP(ETA(1)) Q3 = THETA(3) V3 = THETA(4) CL = THETA(5)*EXP(ETA(2)) ALAG1= THETA(6) ;-------------PK metabolite PK parameters --------------------------------------- V4 = THETA(7) CLM1 = THETA(8)*EXP(ETA(3)) V5 = THETA(9) TVCLM2 = THETA(10) CLM2=TVCLM2 FM1=THETA(11) ; fraction of parent compound converted to M1 ; (1-FM1) ; fraction of the parent compound converted to M2 ;----parameters EHC---------------------------- K46=THETA(12) K62=THETA(13) ;-----TIMES MTIME(1)= THETA(14) MTIME(2)= MTIME(1)+THETA(15) S4=V4 S5=V5 S2=V2 ;-----------initialization metabolite compartments----------------------------- A_INITIAL(4)=1 A_INITIAL(5)=1 ;------------------------------------------------------- K32=Q3/V2 K23=Q3/V3 ;-------------------------------------------------------- $DES FLAG=MPAST(1)-MPAST(2) DADT(1)= -KA*A(1) DADT(2)=KA*A(1)-FM1*(CL/V2)*A(2)-(1-FM1)*(CL/V2)*A(2)+K32*A(3)-K23*A(2)+K62*A(6)*FLAG DADT(3)=K23*A(2)-K32*A(3) DADT(4)=FM1*(CL/V2)*A(2)-K40*A(4)-K46*A(4) DADT(5)=(1-FM1)*(CL/V2)*A(2)-K50*A(5) DADT(6)=K46*A(4)-K62*A(6)*FLAG ;---------------------------------- $ERROR IPRED=F W=IPRED IF(GRP.EQ.2) Y=IPRED+W*EPS(1) ;PARENT IF(GRP.EQ.4) Y=IPRED+W*EPS(2) ;M1 IF(GRP.EQ.5) Y=IPRED+W*EPS(3) ;M2 IRES= DV-IPRED IWR ES= IRES/(W+0.0001) ;------------------------------INITIAL ESTIMATES-------------------------------- $THETA (0,2.37) ;KA $THETA (0,21.7) ;V2 $THETA (0,815) ;Q3 $THETA (0,25700) ;V3 $THETA (0,342) ;CL $THETA (0,0.266) ;ALAG1 $THETA 1 FIX ;V4 $THETA (0,0.99) ;CLM1 $THETA 1 FIX ;V5 $THETA (0,0.99) ;CLM2 $THETA (0,0.7) ;FM1 $THETA (0,0.1 ) ;K46 $THETA (0,5) ;K62 $THETA (0,6) ;MTIME1, theta14 $THETA (0,4) ;theta15 $OMEGA 0.25 0.25 0.25 $SIGMA 0.25 0.25 0.25 $EST MAXEVAL=9000 ...... $COV $TABLE ID… etc…. Then my questions are , 1)is it correct this code if I have a multiple dosing regimen as it is my case???? 2)Does MTIME(1) represent the time at which the EHC begins and MTIME(2) the time at which the EHC finishes? Then if it starts at around 6 hours and finishes at around 10 hours, is it correct to set initital estimates of MTIME (1) and theta (15 ) around 6 and 4 , respectively? In the case I wish to consider a zero order gallbladder emptying , then the correct code would be the following??? ……… DADT(2)=KA*A(1)-FM1*(CL/V2)*A(2)-(1-FM1)*(CL/V2)*A(2)+K32*A(3)-K23*A(2)+(A(6)/DGB)*FLAG DADT(4)=FM*(CL/V2)*A(2)-K40*A(4)-K46*A(4) DADT(5)=(1-FM)*(CL/V2)*A(2)-K50*A(5) DADT(6)=K46*A(4)-(A(6)/DGB)*FLAG Where, DGB would be the duration of gallbladder emptying? When i tried the first order gallbladder emptying i got the following values for MTIME1 (theta14) and theta15 of 94 and 116 , respectively does it have sense? Another thing is that when I run the model I get the following messages (before , one file copied, starting nonmem execution………): Warning 80, $pk sets MTIME but not MTDIFF. When an element of MTIME is reset, then $PK should also set MTDIFF=1, Warning 48, DES-defined items are computed onlu when event time increase , e.g. displayed values associated with the first event record of an individual record are computed with the last advance to> an event time of the prior individual record. What do these messages mean? Is there anything wrong in my code???? I have no experience with this EHC models and i am a little lost. I would be very grateful if anyone could help me Thanks in advance for all Joan ______________________________________________________________________________________________ UNIVERSITY OF CAPE TOWN This e-mail is subject to the UCT ICT policies and e-mail disclaimer published on our website at http://www.uct.ac.za/about/policies/emaildisclaimer/ or obtainable from +27 21 650 4500. This e-mail is intended only for the person(s) to whom it is addressed. If the e-mail has reached you in error, please notify the author. If you are not the intended recipient of the e-mail you may not use, disclose, copy, redirect or print the content. If this e-mail is not related to the business of UCT it is sent by the sender in the sender's individual capacity. _____________________________________________________________________________________________________