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Re: Scaling for pediatric study planning

From: Leonid Gibiansky <LGibiansky>
Date: Fri, 19 Sep 2008 12:07:25 -0400

Joe,
We could be talking about different VM definitions
I am thinking about the model

DADT(1)= -A(1)*VM/(KM+C1) - K10*A(1)

If we believe that the ratio of linear to nonlinear elimination should
not depend on WT (?), then k10 and VM should be scaled similarly ~
WT**(-0.25)

If we present the same equation as

DADT(1)= -C1*VM'/(KM+C1) - K10*A(1)

then
DADT(1)= -A(1)*(VM'/V1)/(KM+C1) - K10*A(1)

VM' is indeed should be scaled as WT**0.75 (thus leading to VM scaled as
WT**(-0.25).

Leonid

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




Joseph Standing wrote:
> Here's my philosophy:
>
> c) VM scales to wt**0.75 as it is a measure of enzyme concentration and
> liver volume relative to body size goes wt**0.75 (Johnson TN et al. 2005) -
> any age-related differences to this are due to developmental factors.
> d) KM - don't scale it, it is a measure of enzyme affinity and shouldn't
> change with size, differences are due to polymorphisms.
> BW,
>
> Joe
>
>
> -----Original Message-----
> From: owner-nmusers
> Behalf Of Leonid Gibiansky
> Sent: den 19 september 2008 17:21
> To: Joachim.Grevel
> Cc: nmusers
> Subject: Re: [NMusers] Scaling for pediatric study planning
>
> 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 - 12:07:25 EDT

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