Nick,
My apologies for labouring the point. I had read your reply as implying
that an assumption about F (or V) was a necessary part of the model.
With metabolite models, this perception is widespread (and often
repeated, sometimes even on nmusers) and I just wanted to be absolutely
clear on
Nick Holford wrote:
Non-proportionality (aka non-linearity) of metabolite formation from
parent is not really an issue. With the right design (i.e. suitable
doses of parent) then this can be discovered from just giving the
parent.
The key assumptions of metabolite models are about how the
James, Mahesh,
The F=1 fallacy has caused me no end of stress over the years, and
next time I may have to contend with the (almost irrefutable) argument
but Nick Holford said it was true.
As I never said this was a fallacy I dont think you need be stressed by
it. Everytime you use a model to
Dear Dr. Holford,
All I was suggesting was that once you have decided on which assumption you
like the most and start modeling the metabolite data then shouldn't
simultaneous modeling of the parent + metabolite be more preferable? The model
will take long run time any ways because it will be a
Ziad:
When FDA sends out a request, there should be a rationale for it. If it
is not clear enough, the sponsors should ask for clarification. If after
clarification, the sponsors felt the rationale is not scientific, then
the sponsors should not hesitate to appeal such requests. The sponsors
can
Hi Nick,
You have written many things that are true, however I think we are
differing on a very essential point.
Nick Holford wrote
Everytime you use a model to describe oral PK data alone you must
make an assumption about the dose that is absorbed.
You could make an assumption about this if
James,
I tried to deal with this in my previous reply. We do not differ. It is
fine for me if you make the assumption that you do not know Fm and you
estimate CLm/Fm and Vm/Fm. But this assumption in practice is an
assumption that Fm=1 when you actually are estimating the parameters.
There
Hello Alan
I have used a sequential approach in the past as the model was more
stable with lesser run time.
Atul
Venkatesh Atul Bhattaram
Pharmacometrics
Office of Clinical Pharmacology
US Food and Drug Administration
The contents of this message are mine personally and do not necessarily
The argument against the simultaneous approach is that the PD data can
drive the PK model, particulary since the PD data usually has more
variability.
-Original Message-
From: [EMAIL PROTECTED] [mailto:[EMAIL PROTECTED]
On Behalf Of Xiao, Alan
Sent: Tuesday, December 09, 2008 11:02 AM
To:
Hi Atul,
The emails must have crossed. However, this is not the FDA view based
on a recent experience where I have to repeat the analysis using the
simultaneous approach.
Kind regards,
Ziad
Dr Ziad Hussein
Senior Director, Pharmacometrics
ICON Development Solutions
Manchester
United Kingdom
Hi Alan,
I just had a very recent experience few weeks ago for a sequential PopPK
for parent and metabolite that was submitted to the FDA and they came
back and asked for simultaneous modelling.
Whether this is scientific or not the FDA view should be taken into
consideration.
Kind regards,
Hi Alan,
Like Bill mentioned above, the reason why the simultaneous approach rasises
questions is that the PK fitted with the simultaneous method can be quite
sensitive to PD model misspecification.
The publicatiosn below discussed the robusteness and performance of several
secinarios within the
The appropriate approach is to fit parent compound and the metabolites
simultaneously, since it can help uniquely define the PK parameters,
especially the CL. As we know that CL is a lumped parameter without
metabolite information. Sequential estimation is the approach when there
is no
Hi,
Experimental studies (rather than just opinion) can be found here:
1.Zhang L, Beal SL, Sheiner LB. Simultaneous vs. sequential analysis
for population PK/PD data I: best-case performance. J Pharmacokinet
Pharmacodyn. 2003;30(6):387-404.
2.Zhang L, Beal SL, Sheiner LB. Simultaneous
Alan,
The comments about sequential vs simultaneous modelling apply for any
kind of multivariate approach. The 'driver' model e.g. parent conc for
metabolite or the 'driven' model e.g. metabolite from parent will be
dependent on having a good driver model first. If the driver plus driven
Hi Nick,
I hope all is well with you - good to see you are keeping the nmusers in
line :-).
I am not sure I agree with your second paragraph as I have understood
it. When I fit a parent-metabolite model, I estimate CL/F and V/F for
the metabolite. Frequently, I hear the widespread
James,
All is well with me and it seems things continue to be (w)right for you :-)
Non-proportionality (aka non-linearity) of metabolite formation from
parent is not really an issue. With the right design (i.e. suitable
doses of parent) then this can be discovered from just giving the
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