RE: Scaling for pediatric study planning
I can't agree more with Jeff's comments that we should "pursue more
physiologic expressions" and this is a "place where "bottom-up" approaches"
are advantageous.
The allometric scaling may be useful for children older than 2 years but for
younger subjects surely the developmental factors should be considered as
explained in: Johnson TN, Rostami-Hodjegan A and Tucker GT (2006) Prediction
of the clearance of eleven drugs and associated variability in neonates,
infants and children. Clin Pharmacokinet 45:931-956.
Regards
Masoud
Quoted reply history
> -----Original Message-----
> From: [EMAIL PROTECTED] [mailto:owner-
> [EMAIL PROTECTED] On Behalf Of Jeffrey Barrett
> Sent: 19 September 2008 16:54
> To: [EMAIL PROTECTED]; [EMAIL PROTECTED]
> Cc: [email protected]
> Subject: Re: [NMusers] Scaling for pediatric study planning
>
> 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: [EMAIL PROTECTED]
> Ph: (267) 426-5479
>
> >>> Leonid Gibiansky <[EMAIL PROTECTED]> 9/19/2008 11:20 AM
> >>>
> 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
>
>
>
>
> [EMAIL PROTECTED] wrote:
> >
> > 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: [EMAIL PROTECTED]
> >
> >
> -----------------------------------------------------------------------
> -
> >
> > This message and any attachment are confidential, may be privileged
> or
> > otherwise protected from disclosure and are intended only for use by
> the
> > addressee(s) named herein. If you are not the intended recipient, you
>
> > must not copy this message or attachment or disclose the contents to
> any
> > other person. If you have received this transmission in error, please
>
> > notify the sender immediately and delete the message and any
> attachment
> > from your system.