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

From: Nick Holford <n.holford>
Date: Wed, 10 Dec 2008 09:52:01 +1300


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.


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
> 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
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Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New Zealand
Received on Tue Dec 09 2008 - 15:52:01 EST

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