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
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 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
EHC modelling
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
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 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
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
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Hi Joan
You may find the following papers useful.
Jiao Z, Ding JJ, Shen J, Liang HQ, Zhong LJ, Wang Y, Zhong MK and Lu WY
(2008) Population pharmacokinetic modelling for enterohepatic circulation of
mycophenolic acid in healthy Chinese and the influence of polymorphisms in
UGT1A9. Br J Clin Pharmacol 65:893-907.
Yau W-P, Vathsala A, Lou H-X, Zhou S and Chan E (2009) Mechanism-Based
Enterohepatic Circulation Model of Mycophenolic Acid and Its Glucuronide
Metabolite: Assessment of Impact of Cyclosporine Dose in Asian Renal
Transplant Patients. J Clin Pharmacol 49:684-699.
Also, please note that gallbladder is not getting fully emptied when it
contracts and the emptying process is not abrupt. In addition, there are
cases where a part of metabolite may return to the parent form
(deconjugated) when it reaches the small intestine.
Regards
Masoud
Hi Joan
You may find the following papers useful.
Jiao Z, Ding JJ, Shen J, Liang HQ, Zhong LJ, Wang Y, Zhong MK and Lu WY
(2008) Population pharmacokinetic modelling for enterohepatic circulation of
mycophenolic acid in healthy Chinese and the influence of polymorphisms in
UGT1A9. Br J Clin Pharmacol 65:893-907.
Yau W-P, Vathsala A, Lou H-X, Zhou S and Chan E (2009) Mechanism-Based
Enterohepatic Circulation Model of Mycophenolic Acid and Its Glucuronide
Metabolite: Assessment of Impact of Cyclosporine Dose in Asian Renal
Transplant Patients. J Clin Pharmacol 49:684-699.
Also, please note that gallbladder is not getting fully emptied when it
contracts and the emptying process is not abrupt. In addition, there are
cases where a part of metabolite may return to the parent form
(deconjugated) when it reaches the small intestine.
Regards
Masoud