From: Emmanuel Chigutsa <*Emmanuel.Chigutsa*>

Date: Wed, 27 Jan 2010 16:52:28 +0200

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: emmanuel.chigutsa

*>>> joan hern <joanhc0603 *

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)+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

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 IDâ€¦

etcâ€¦.

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???

â€¦â€¦â€¦

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 executionâ€¦â€¦â=

€¦):

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

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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.

___________________________________________________________________________=

__________________________

Received on Wed Jan 27 2010 - 09:52:28 EST

Date: Wed, 27 Jan 2010 16:52:28 +0200

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: emmanuel.chigutsa

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)+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

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 IDâ€¦

etcâ€¦.

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???

â€¦â€¦â€¦

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 executionâ€¦â€¦â=

€¦):

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.

___________________________________________________________________________=

__________________________

Received on Wed Jan 27 2010 - 09:52:28 EST