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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 09:44:46 +1300

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 vs. sequential analysis
for population PK/PD data II: robustness of methods. J Pharmacokinet
Pharmacodyn. 2003;30(6):405-16.
3. Proost JH, Schiere S, Eleveld DJ, Wierda JM. Simultaneous versus
sequential pharmacokinetic-pharmacodynamic population analysis using an
iterative two-stage Bayesian technique. Biopharm Drug Dispos.
2007;28(8):455-73.

My interpretation of these studies is that one should use a sequential
approach to build the model then try a simultaneous fit. If the PK part
of the model changes 'importantly' (subjective decision) with the
simultaneous fit then this can be a clue to model misspecification in
the link between the PK and PD parts of the model (see second paper by
Zhang et al).

Nick


Hussein, Ziad wrote:
> 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,
> Ziad
>
> -----Original Message-----
> From: owner-nmusers
> On Behalf Of Xiao, Alan
> Sent: 09 December 2008 16:02
> 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
n.holford
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
Received on Tue Dec 09 2008 - 15:44:46 EST

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