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Re: RE: Pediatric brain scaling

From: Nick Holford <n.holford>
Date: Tue, 17 Nov 2015 09:24:23 +1300


Thanks for the reference to the study by Matsuzawa et al. This study
involved 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
volumes increase with age. They use a model to describe this which does
not reach 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 think it should be thought of as not changing.

Note also that this study did not measure thecal CSF volumes so it would
require some extrapolation of these ventricular CSF findings to predict
thecal CSF volumes.


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

Anderson BJ, Holford NH, Woollard GA, Chan PL. Paracetamol plasma and
cerebrospinal fluid pharmacokinetics in children. Br J Clin Pharmacol.

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
> <mailto:kluu
> *From:*owner-nmusers
> [mailto:owner-nmusers
> *Sent:* Monday, November 16, 2015 8:56 AM
> *To:* nmusers
> *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. ™
> 2525 Meridian Parkway, Suite 280
> Research Triangle Park, NC 27713
> Office (919)-973-0383
> msale
> <>
> */Empower your Pipeline/*
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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

Holford SD, Allegaert K, Anderson BJ, Kukanich B, Sousa AB, Steinman A, Pypendop, B., Mehvar, R., Giorgi, M., Holford,N.H.G. Parent-metabolite pharmacokinetic models - tests of assumptions and predictions. Journal of Pharmacology & 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 - 15:24:23 EST

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