RE: Simultaneous drug and metabolite POPPK
Alan,
I am afraid that you didnt read my code carefully enough. Actually, Eqs 1-3
are talking about the SAME thing, ie, metabolite rate. I started out with the
full data, i.e., with IV info available (Eq1), then, tried to illustrate the
issue when IV data is not available (Eq2) and finally, show how this can be
coded in NONMEM in view of the constraint in order to fit the data (Eq3).
All I tried to say is that there are many other identifiability issues can NOT
be addressed with this type of data by modeling (i.e., model P and Met when
only P is administrated, and more than one metabs are formed). Given this fact,
conversion to molar unit becomes less critical (although it is a good
practice). One should be always cautious when interpret the parameter obtained
on its physiological meaning (even if you have concerted to molar unit).
Jun
Quoted reply history
-----Original Message-----
From: Xiao, Alan [mailto:[EMAIL PROTECTED]
Sent: Tue 2/13/2007 5:22 PM
To: Shi, Jun; [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Hmm,
I wonder how you write the mass balance equation for the parent and how to
define parameter KMP. If you use the same term KMP(iv)*A(2) in both equations
for the parent [DADT(2)=...-KMP(iv)*A(2)] and the metabolite (DADT(3)=...],
then this same term have different physical meaning in two equations if weight
concentrations are used. I think you don't want to use the same term to
represent two different things (and two different quantities) in your mass
balance equations although you may still get fitting perfect.
In addition, for simultaneously modeling parent/metabolite data, yes, if you
don't have iv data for metabolite, you can not get a unique set of parameter
estimates for metabolites because of overparameterization. However, if you have
prior information about metabolic ratios, you can fix that into your model,
such as Kel_met_parent / Kel_tot_parent=R (e.g. 0.5), where Kel_met_parent is
elimination rate constant of the parent through metabolism of interest and
Kel_tot_parent is the total elimination rate constant of the parent, so R is
called metabolic ratio. Once this ratio is available, volume of distribution
for metabolites are estimable if data is informative.
They might be other options to handle the issue as well.
Alan
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] Behalf Of Shi, Jun
Sent: Tuesday, February 13, 2007 10:50 AM
To: [EMAIL PROTECTED]; Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
Mike,
This depends on the purpose of the modeling and the information available.
Usually, we only have Parent and Met concentration data after oral
administration, therefore, we can't estimate the true disposition parameters.
We can get CL/F and V/F for parent, but we can get nothing more than apparent
Production rate constant and Elimination rate constant for Met. In this case,
converting the data to micromolar unit or not is not critical.
e.g.
Let's begin from the differential equation below:
DADT(3)=KMP(iv)*A(2)-KME*A(3)
Eq 1
where A(2) is the amount of parent (mg), A(3) is the amount of metabolite (mg).
KmP is the production rate of the metabolite.
Because the distribution volume of Met (V3) is unobtainable (no IV data of
Met), we have to convert dA/dt to dC/dt and divide both sides of Eq 1 by V3 as
follows:
DADT(3)/V3=KMP(iv)*A(2)/V3-KME*A(3)/V3 Eq 2
In NONMEM, we coded this as follows:
DADT(3)=KMP *A(2)/V2-KME*A(3)
Eq 3
Please note that DADT(3) in Eq 3, actually, is dC3/dt (a rate of concentration
instead of amount), and KMP in Eq 3 = KMP(iv) x V2/V3 in Eq 1. In other words,
KMP is a composite parameter of both volumn ratio and molecular weight ratio.
If there are IV data for both parent and metabolite after administrations of
parent and metabolite seperately, the true disposition parameters can be
estimated for both. By converting the concentration unit to molar, we can
estimate formation fraction of parent to metabolite.
Jun Shi
Clinical Pharmacology and Drug Dynamics
Forest Research Institute
Rm18-35
Harborside Financial Center-Plaza V
Jersey City, NJ 07311
Tel: 201-427-8044
Fax: 201-427-8498
Email: [EMAIL PROTECTED]
-----Original Message-----
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED] On Behalf Of [EMAIL PROTECTED]
Sent: Tuesday, February 13, 2007 9:02 AM
To: Nmusers (E-mail); [EMAIL PROTECTED]
Subject: RE: [NMusers] Simultaneous drug and metabolite POPPK
I have a question for those who submitted these two examples - Did you
transform the data into micromolar quantities? It is not clear from the
examples. I have not done much parent/metabolite modeling (just lucky I guess)
but it seems to me that one would have to work in molar units for these models
to be valid. Can someone comment on this?
Mike
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Michael J. Fossler, Pharm. D., Ph. D., F.C.P.
Director
Clinical Pharmacokinetics, Modeling & Simulation
GlaxoSmithKline
(610) 270 - 4797
FAX: (610) 270-5962
Cell: (443) 350-1194
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