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RE: Your suggestions/thoughts needed on allometric base or final model

From: James G Wright <james>
Date: Wed, 16 Jul 2008 00:53:28 +0100

Hi Nick,

Perhaps I am foolish, as I must be misunderstanding your point.

If the goal is predicting concentrations, I struggle to imagine a
situation where knowing a covariate is anywhere near as valuable as
knowing the dose administered. Dose appears explicitly in
pharmacokinetic formulae and concentrations are typically proportional
to dose. Weight is just a covariate, meaning that it can improve your
guess of the pharmacokinetic parameters. It's not even a particularly
good covariate...

Best regards, James

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


-----Original Message-----
From: owner-nmusers
On Behalf Of Nick Holford
Sent: 15 July 2008 23:05
To: nmusers
Subject: Re: [NMusers] Your suggestions/thoughts needed on allometric
base or final model

James,

Intepretation of my remarks implicitly requires that you consider "all
other things being equal" e.g. if the dose is doubled but the patient
does not take the dose then the concentration will not double. I think
dose and weight are equally important for predicting concentrations --
all other things being equal.

I did not write this and do not agree with it:

"Weight is always important, in that it should alter dose selection"

I can accept that weight based dosing may be unnecessary if other
sources of variability are much larger but my remarks were made in the
context of trying to describe the PK parameters of a drug. To imagine
that clearance and volume are not related to weight is just foolish.

Nick

James G Wright wrote:
>> Nick Holford wrote:
>>
>
>
>> Body weight is always important (in adults and children) even if the
>> data set you are studying is inadequate to reject a null hypothesis
>> because of unsuitable design.
>>
>
>
> The truth of this statement depends on what you mean by "important".
> Dose is important because, for the majority of drugs, doubling dose
> doubles plasma exposure, and this can lead to changes in side-effects
> and/or efficacy. The effect of dose is fundamental to PK for 3
reasons:
> 1) It's magnitude - dose usually has a big effect on PK.
> 2) Dose is partially controlled by the prescriber
> 3) AUC is proportional to dose for the majority of drugs, with
> an intercept of zero.
>
> Comparing weight to dose seems to be stretching the point just a
little.
> I would be happy to accept the statement:
>
> "Weight always has some effect on pharmacokinetics, though it may be
so
> small as to be practically irrelevant"
>
> But that is a long way from:
>
> "Weight is always important, in that it should alter dose selection"
>
> Best regards, James
>
> James G Wright PhD
> Scientist
> Wright Dose Ltd
> Tel: 44 (0) 772 5636914
>
>
> -----Original Message-----
> From: owner-nmusers
[mailto:owner-nmusers
> On Behalf Of Nick Holford
> Sent: 14 July 2008 05:32
> To: nmusers
> Subject: Re: [NMusers] Your suggestions/thoughts needed on allometric
> base or final model
>
> Atul,
>
> As Steve Duffull has pointed out you can decide to be an empiricist
and
> ignore all prior biological knowledge and try to estimate empirically
an
>
> allometric coefficient or you can put trust in prior knowledge which
> means PK parameters such as clearance will increase with weight.
> Empiricists will often misinterpret their statistical tests to
conclude
> there is no association between weight and PK parameters when in fact
> the weight distribution is inadequate or they have not properly
> acccounted for important factors such as body composition.
>
> If you believe in biology then it is foolish in most cases to attempt
to
>
> estimate an allometric coefficient because the estimate will be biased

> unless you have a very informative weight distribution and good
> estimates of PK parameters (dont bother if you are relying on sparse
PK
> sampling methods). See Anderson, B.J. and N.H. Holford,
> Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics.
Annu
> Rev Pharmacol Toxicol, 2008. 48: p. 303-332. for a discussion of the
> problem and experimental evidence of the difficulties in assessing
> allometric coefficients.
>
> Body weight is always important (in adults and children) even if the
> data set you are studying is inadequate to reject a null hypothesis
> because of unsuitable design.
>
> Hong-Guang,
>
> In my opinion all PK *base* models will include allometric weight
> scaling of clearance and volume. If you ignore weight then is is like
> ignoring dose in PK models. Both weight and dose are fundamental
> covariates for predicting drug concentrations.
>
> Nick
>
> Bhattaram, Atul wrote:
>
>> Hello Hong-Guang
>>
>>
>>
>> It is always a good idea to estimate the allometric coefficient if
you
>>
>
>
>> have adequate (weight ranges, PK sampling etc) data collected. If
>> body weight is not important (although that is rare in pediatrics),
>> then it need not be included in the model.
>>
>>
>>
>> Atul
>>
>>
>>
>> Venkatesh Atul Bhattaram
>> Pharmacometrics
>> US Food and Drug Administration
>>
>>
>> "The contents of this message are mine personally and do not
>> necessarily reflect any position of the Government or the Food and
>> Drug Administration."
>>
>>
>>
>>
>>
>
------------------------------------------------------------------------
>
>> *From:* owner-nmusers
>> [mailto:owner-nmusers
>>
> Xie
>
>> *Sent:* Friday, July 11, 2008 12:36 PM
>> *To:* nmusers
>> *Subject:* [NMusers] Your suggestions/thoughts needed on
>> allometric base or final model
>>
>> Dear NMusers:
>>
>>
>>
>> As you know, body weight is an important covariate that is
>> integrated into the final or covariate model in some cases. When
>> analyzing pediatric pop PK data, body weight-based allometric
>> power model is used frequently. By definition, base model is a
>> model without any covariates. But, in the literature on the
>> population PK in pediatrics, I noted that body weight is added to
>> the structural model (following the principles of allometry)
>> before starting the covariate model building in some but not in
>> all studies. That means that some models are called allometric
>> base models and others are not. What are their differences? For
>> the allometric base model, body weight has been added into the
>> base model regardless of whether it is an important covariate (in
>> some cases, body weight is not). If body weight is not an
>> important covariate as determined by further covariate model
>> building, is there still the need to add body weight into the
>> final allometric model (if its corresponding base model is one
>> without a body weight-associated allometric component)?
Logically,
>> such a need seems to be not reasonable. How to deal with this
>> conflict? Is there an almost agreeable thought on this issue in
>> our community?
>>
>>
>>
>> Thank you,
>>
>>
>>
>> Hong-Guang
>>
>>
>
>

--
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 Jul 15 2008 - 19:53:28 EDT

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