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RE: [NMusers] RE: Pediatric brain scaling

From: Ken Luu <KLuu_at_isisph.com>
Date: Mon, 16 Nov 2015 21:16:05 +0000

Thanks for clarifying, Nick. I agree. We did use the equation for calcula=
ting the predicted CSF volume for infants. The slope between 0 and 24 mont=
hs is 0.8, whereas the slope between 30 to 132 months is 0.2. To be more =
accurate, I should have said that it "it does not change MUCH after two yea=
rs."

Ken

-----Original Message-----
From: owner-nmusers_at_globomaxnm.com [mailto:owner-nmusers_at_globomaxnm.com] On=
 Behalf Of Nick Holford
Sent: Monday, November 16, 2015 12:24 PM
To: nmusers_at_globomaxnm.com
Subject: Re: [NMusers] RE: Pediatric brain scaling

Ken,

Thanks for the reference to the study by Matsuzawa et al. This study involv=
ed infants and children up to 10 y old plus some adult values.

I think it is a bit misleading to say CSF volume does not change after 2 y.

The authors show that white matter, grey matter and supra-tentorial CSF vol=
umes increase with age. They use a model to describe this which does not re=
ach a constant value e.g for CSF:
Z=ln(age/100) + 0.7596
CSF=149.88 + 13.9*Z

While I agree the increase in CSF volume is gradual after 2 years I don't t=
hink it should be thought of as not changing.

Note also that this study did not measure thecal CSF volumes so it would re=
quire some extrapolation of these ventricular CSF findings to predict theca=
l CSF volumes.

Mark,

An semi-empirical approach to describing "brain clearance" has been used to=
 describe paracetamol ventricular CSF concs in relation to plasma concs. Th=
is method uses an effect compartment to account for a distribution delay to=
 the CSF with theory based allometry to scale the effect compartment equili=
bration rate constant (proportional to "brain clearance").

Anderson BJ, Holford NH, Woollard GA, Chan PL. Paracetamol plasma and cereb=
rospinal fluid pharmacokinetics in children. Br J Clin Pharmacol.
1998;46(3):237-43.


On 17-Nov-15 07:25, Ken Luu wrote:
>
> Hi Mark,
>
> I've recently developed a popPK model for an IT dosed drug in infants
> (0-2yrs) and children (2-15yrs), median age for all studies were 5 yo.
> The work has not been published yet as the clinical development
> program is ongoing.
>
> Some background: The basis of the dosing scheme for this drug was
> theoretically derived (prior to any modeling) based on predicted CSF
> volume rather than brain weight. In the publication: Matsuzawa, J.,
> et al. (2001). "Age-related volumetric changes of brain gray and white
> matter in healthy infants and children." Cereb Cortex 11(4): 335-342,
> CSF volume changes for infants up to 2 years but does not change as
> they age after 2 years. For this reason, the original clinical
> program dosed infants based on age and children at a fixed dose.
>
> In my model (unfortunately, a lot of it I cannot share at this time),
> I had sparse CSF concentrations measured along with sparse and rich
> sampling concentrations in plasma. The model simultaneously fit CSF
> and Plasma profiles. In the covariate analysis, either AGE or BWT was
> a statistically significant covariate to Vcsf (CSF volume of
> distribution). The relation identified was a piece-wise ("hockey
> stick") relation. Neither AGE for BWT was influential on CLcsf. The
> final model (thanked God) supported the original dosing rationale.
>
> When I was starting this work I couldn't find anything on this topic
> either. I hope this helps in thinking in terms of CSF volume instead
> of brain weight, if it's relevant to your compound.
>
> Ken
>
> *Kenneth T. Luu, Ph.D.*
>
> Director | PK & Clinical Pharmacology
>
> Isis Pharmaceuticals, Inc. | 2855 Gazelle Ct Carlsbad, CA 92010
> Office: 760.603.2457 | Fax: 760-603-2502 | Email: kluu_at_isisph.com
> <mailto:kluu_at_isisph.com>
>
> *From:*owner-nmusers_at_globomaxnm.com
> [mailto:owner-nmusers_at_globomaxnm.com] *On Behalf Of *Mark Sale
> *Sent:* Monday, November 16, 2015 8:56 AM
> *To:* nmusers_at_globomaxnm.com
> *Subject:* [NMusers] Pediatric brain scaling
>
> Dear Colleagues,
>
> I'm working on a drug that is administered intrathecally to kids and
> adults. I'm interested in scaling pk from adults to kids (whose brains
> start out relatively large, compared to the body, but reach maximum
> size in the teens, then stop growing). I'm a little surprised that I
> can't find anything about dosing CNS drugs to peds, based on brain
> weight (and, ideally, brain clearance). Does anyone know of anything?
>
> thanks
>
> Mark
>
> Mark Sale M.D.
>
> Vice President, Modeling and Simulation
>
> Nuventra, Inc. (tm)
>
> 2525 Meridian Parkway, Suite 280
>
> Research Triangle Park, NC 27713
>
> Office (919)-973-0383
>
> msale_at_nuventra.com <msale_at_kinetigen.com>
>
> www.nuventra.com <http://www.nuventra.com>
>
> */Empower your Pipeline/*
>
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> attachments, if any) may be privileged and confidential and is
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--
Nick Holford, Professor Clinical Pharmacology
Dept Pharmacology & Clinical Pharmacology, Bldg 503 Room 302A
University of Auckland,85 Park Rd,Private Bag 92019,Auckland,New Zealand
office:+64(9)923-6730 mobile:NZ+64(21)46 23 53
email: n.holford_at_auckland.ac.nz
http://holford.fmhs.auckland.ac.nz/

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pyp=
endop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmac=
okinetic models - tests of assumptions and predictions. Journal of Pharmaco=
logy & Clinical Toxicology. 2014;2(2):1023-34.
Holford N. Clinical pharmacology = disease progression + drug action. Br =
J Clin Pharmacol. 2015;79(1):18-27.

Received on Mon Nov 16 2015 - 16:16:05 EST

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