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Re: Scaling for pediatric study planning

From: Jeffrey Barrett <barrettj>
Date: Fri, 19 Sep 2008 11:53:38 -0400

Leonid / Joachim,

I think we're pushing the envelope on empiricism here. Two facts of
reality prevail here:

1) we seldom collect enough data during the absorption phase to assess
any meaningful age/developmental dependencies across the age continuum.
The fisrt-order assumption is always bad even in adults but we live with
it because we seldom have absorption as a primary phase of interest.

2) a physiologic approach, in addition to a more fundamental
approximation of reality also has more options with respect to
functional expressions that can accomodate developmental factors such as
changes in pH dependency, the surface area of the GI tract, or the site
and expression of presystemic P450 enzymes all of which factor into the
size surrogacy issue.

Hence, I'm not sure that I would consider the allometric
characterization of absorption in the same manner as one would treat CL
or V considerations as it is indeed a hybrid process. I will defer to
Nick's wisdom on this but if I am pressed for a guess, I would not scale
but pursue more physiologic expressions. In actuality, this is a place
where "bottom-up" approaches would seem to have a decided advantage.

Jeff



Jeffrey S. Barrett, Ph.D., FCP
Research Associate Professor, Pediatrics
Director, Pediatric Pharmacology Research Unit,
Laboratory for Applied PK/PD
Clinical Pharmacology & Therapeutics
Abramson Research Center, Rm 916H
The Children's Hospital of Philadelphia
3615 Civic Center Blvd.
Philadelphia, PA 19104

KMAS (Kinetic Modeling & Simulation)
Institute for Translational Medicine
University of Pennsylvania
email: barrettj
Ph: (267) 426-5479

>>> Leonid Gibiansky <LGibiansky
>>>
Just to add:

c) how do we allometrically scale a VM rate constant of the
Michaelis-Menten elimination model:

C1=A(1)/V1
DADT(1)= ... -A(1)*VM/(KM+C1)

d) do we need to allometrically scale a KM constant of the
Michaelis-Menten elimination model ?

any experience with these quantities (for example, if they were
estimated, what were the estimates, with the precision)?


My suggestion would be NOT to scale a), b) and d), and scale VM as the

rate constant (~ WT**(-0.25)) but I do not have "rock-solid" data to
support those suggestions.

Leonid
--------------------------------------
Leonid Gibiansky, Ph.D.
President, QuantPharm LLC
web: www.quantpharm.com
e-mail: LGibiansky at quantpharm.com
tel: (301) 767 5566




Joachim.Grevel
>
> Dear NM_Users,
>
> we have all been good students and listened to Nick when he told us
> again and again the rock-solid truths of allometry:
>
> Volume: *(WT/70)
>
> CL: *(WT/70)**0.75
>
> any rate constant related to distribution or elimination:
*(WT/70)**(-0.25)
>
> Here my questions:
> a) how do we allometrically scale a first-order rate constant of
> absorption after oral dosing?
>
> b) how do we allometrically scale a first-order rate constant of
> absorption from a subcutaneous injection site?
>
> Thank you for your thoughts,
>
> Joachim
>
> __________________________________________
> Joachim GREVEL, Ph.D.
> MERCK SERONO International S.A.
> Exploratory Medicine
> 1202 Geneva
> Tel: +41.22.414.4751
> Fax: +41.22.414.3059
> Email: joachim.grevel
>
>
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Received on Fri Sep 19 2008 - 11:53:38 EDT

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