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
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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.
Ken,
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.
Mark,
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 clearance").
Anderson BJ, Holford NH, Woollard GA, Chan PL. Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children. Br J Clin Pharmacol. 1998;46(3):237-43.
Quoted reply history
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: [email protected] < mailto: [email protected] >
>
> *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. ™
>
> 2525 Meridian Parkway, Suite 280
>
> Research Triangle Park, NC 27713
>
> Office (919)-973-0383
>
> [email protected] <[email protected]>
>
> www.nuventra.com 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.
--
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: [email protected]
http://holford.fmhs.auckland.ac.nz/
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.