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

From: James G Wright <james>
Date: Wed, 10 Dec 2008 12:09:32 -0000

>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

The key assumptions of metabolite models are about how the metabolite is
formed - linearly or nonlinearly, from plasma or during first-pass,
immediately or not. Making sure your assumptions are true is really the
issue for me with any analysis.

>But to really know how much of the parent is eventually
>transformed to the metabolite needs additional information i.e. direct
>administration of the metabolite.

Of course, if fraction formed is the parameter that you need to

Fitting a metabolite PK model is not dependent on assuming 100%
metabolite formation from parent, as you originally stated, unless you
mislabel the parameters as actual CL, instead of CL/F. Not knowing F
doesn't affect the application and predictive utility of the model any
more than not knowing F for the parent after oral administration.

The widespread presentation of "F=1" as an "unverifiable assumption"
causes model end-users to suspect that the assumption could in some
sense be wrong ("Aah, but how do you know F=1?"), leading to the
perception that the metabolite model is misleading and unreliable.

I think it would be helpful if you could explicitly retract your
assertion regarding the assumption "that all drug goes to metabolite".
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".

Best regards, James

James G Wright wrote:
> Hi Nick,
> I hope all is well with you - good to see you are keeping the nmusers
> 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
> 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
> 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
> 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
> data
>> first and then fix the PK parameters for parents to develop a model
>> to fit the metabolite. While, for simultaneous approach, you develop
> 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
>> "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
> 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
Received on Wed Dec 10 2008 - 07:09:32 EST

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