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RE: Simultaneous vs sequential for modeling parent AND metabolites in pop PK

From: James G Wright <james>
Date: Tue, 9 Dec 2008 22:44:12 -0000

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 misconception that I
have assumed all of the parent goes to metabolite, but this would only
be true if I claimed to have estimated CL, rather than CL/F. This is
exactly the same as if I analyse the parent after oral administration
(without IV) - we don't assume all the drug is absorbed, we simply
estimated the ratio of CL and V to F.

The real assumption lies in the form of the link between parent and
metabolite - for example, that it is linearly formed from parent in
plasma. It is this assumption that may need to be more rigorously
evaluated, and exactly the point highlighted in your first paragraph.
For example, there can be an apparent delay in metabolite formation
relative to parent plasma concentrations and/or the metabolite may be
formed during the first-pass.

Best regards, James

PS One can get technical and claim there needs to be a correction for
molecular weight in F for the metabolite, but the importance of this
depends on how the parameter will actually be used.

James G Wright PhD
Scientist
Wright Dose Ltd
Tel: 44 (0) 772 5636914


-----Original Message-----
From: owner-nmusers
On Behalf Of Nick Holford
Sent: 09 December 2008 20:52
To: nmusers
Subject: Re: [NMusers] Simultaneous vs sequential for modeling parent
AND metabolites in pop PK

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

dont do well together with a simultaneous fit then this is a clue to
model misspecification.

Parent-metabolite models nearly always have to make at least one
unverifiable assumption if the metabolite is not given directly. (e.g.
one may assume all of the parent goes to metabolite OR assume a volume
for the metabolite). PKPD models also have unverifiable assumptions e.g.

concentration at the site of the drug effect.

Nick

Xiao, Alan wrote:
> Dear All,
>
> Thanks for your response and I'm sorry for the confusion.
>
> I'm talking about the sequential/simultaneous modeling to fit parent
> concentrations AND metabolites in pop PK, not about PD data at all.
>
> That is for sequential approach, you develop a model to fit the parent
data
> first and then fix the PK parameters for parents to develop a model
> to fit the metabolite. While, for simultaneous approach, you develop a
model to
> fit both parent and metabolites simultaneously
> (to simultaneously estimate parameters for both parent and
metabolites).
>
> Alan
>
> -----Original Message-----
> From: Bachman, William [mailto:William.Bachman
> Sent: Tuesday, December 09, 2008 11:26 AM
> To: Xiao, Alan
> Cc: nmusers
> Subject: RE: [NMusers] Simultaneous vs sequential for modeling parent
> AND metabolites in pop PK
>
>
> 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: owner-nmusers
[mailto:owner-nmusers
> On Behalf Of Xiao, Alan
> Sent: Tuesday, December 09, 2008 11:02 AM
> To: nmusers
> Subject: [NMusers] Simultaneous vs sequential for modeling parent AND
> metabolites in pop PK
>
> Dear All,
>
> I know this is an old topic but would like to see the statistics.
>
> When you have to develop a pop PK model for both parent and active
> metabolites, which approach do you prefer or have you used most:
> simultaneous or sequential? Which way do you think is more scientific?
I
> heard comments saying that the simultaneous approach is not
scientific.
>
> Thanks,
>
> Alan
> ICON plc made the following annotations.
>
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--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
Received on Tue Dec 09 2008 - 17:44:12 EST

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