[NMusers] RE: Pediatric brain scaling

From: Ken Luu <KLuu_at_isisph.com>
Date: Mon, 16 Nov 2015 18:25:22 +0000

Hi Mark,

I've recently developed a popPK model for an IT dosed drug in infants (0-2y=
rs) 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 theoretic=
ally derived (prior to any modeling) based on predicted CSF volume rather t=
han brain weight. In the publication: Matsuzawa, J., et al. (2001). "Age-r=
elated 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 rea=
son, 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 con=
centrations in plasma. The model simultaneously fit CSF and Plasma profile=
s. In the covariate analysis, either AGE or BWT was a statistically signif=
icant covariate to Vcsf (CSF volume of distribution). The relation identif=
ied was a piece-wise ("hockey stick") relation. Neither AGE for BWT was in=
fluential on CLcsf. The final model (thanked God) supported the original d=
osing 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 we=
ight, 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:kl=
uu_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 adul=
ts. I'm interested in scaling pk from adults to kids (whose brains start ou=
t relatively large, compared to the body, but reach maximum size in the tee=
ns, 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>



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Received on Mon Nov 16 2015 - 13:25:22 EST

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