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EHC modelling

From: joan hern <joanhc0603>
Date: Wed, 27 Jan 2010 12:26:31 +0100

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 cod=
e
(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)+K=
62*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
  IWRES= 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 an=
d
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 value=
s
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 b=
e
very grateful if anyone could help me
Thanks in advance for all
Joan

Received on Wed Jan 27 2010 - 06:26:31 EST

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