RE: Pediatric brain scaling
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:
[email protected]<mailto:[email protected]>
Quoted reply history
From: [email protected] [mailto:[email protected]] On
Behalf Of Mark Sale
Sent: Monday, November 16, 2015 8:56 AM
To: [email protected]
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
[email protected]<[email protected]>
http://www.nuventra.com
Empower your Pipeline
CONFIDENTIALITY NOTICE The information in this transmittal (including
attachments, if any) may be privileged and confidential and is intended only
for the recipient(s) listed above. Any review, use, disclosure, distribution or
copying of this transmittal, in any form, is prohibited except by or on behalf
of the intended recipient(s). If you have received this transmittal in error,
please notify me immediately by reply email and destroy all copies of the
transmittal.