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Hello,
I would like to pose a question.
In a discussion with a colleague it was suggested that:
"The brain-to-plasma ratio for a compound be derived from the Cmax in
brain over the Cmax from plasma."
It was said that "this is an acceptable, industry wide practice to
derive the brain-to-plasma ratio in this manner."
Is this true, and if so, how is using this method of calculating the
brain-to-plasma justified?
Thank You
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[And even more messages - db]
=46rom: "Masson, =C9ric"
To: "'PharmPK.aaa.boomer.org'"
Subject: RE: PharmPK A Brain-to-Plasma Ratio Question
Date: Thu, 24 Feb 2000 08:59:11 -0500
Looking at ratios of Cmax is misleading. The time course of Brain or CSF
levels is usually different from that of plasma. If multiple sampling is
feasible, looking at AUC ratio is probably a better approach.
Eric masson
Scientific Director
emasson.-at-.anapharm.com
---
=46rom: "Melethil, Srikumaran K."
To: "'PharmPK.-at-.boomer.org'"
Subject: RE: PharmPK A Brain-to-Plasma Ratio Question
Date: Thu, 24 Feb 2000 10:00:21 -0600
Dear Todd,
=46irst, why does one do such an experiment? Obviously, it is to get some=
idea of
the distribution of the drug into the brain. For brain to plasma ratios to =
be
meaningful, the two regions must be in equilibrium. Therefore, peak ratios =
in
some cases may be satisfactory, since some time is allowed for such
equilibration.
Sri
Sri Melethil, Ph.D.
Professor of Pharmaceutics and Medicine
University of Missouri-KC
School of Pharmacy
Room 203-B, 5005 Rockhilll Road
Kansas City, MO 64110
816-235-1794 (fax: 816-235-5190)
---
=46rom: "Patrick Smith, Pharm.D."
To:
Subject: RE: PharmPK A Brain-to-Plasma Ratio Question
Date: Thu, 24 Feb 2000 12:01:54 -0500
X-Priority: 3 (Normal)
Importance: Normal
I have a difficult time rationalizing this approach, as the Cmax in plasma
will be disjointed from the cmax in csf, or wherever you are measuring
concentrations in 'the brain'.
It is clear that plasma and csf concentrations should be measured
simultaneously to get the most accurate representation of concentrations. If
using a single concentrations for the comparison, it is more logical to
compare Cmin values, therefore allowing time for equilibration between the
two compartments to occur.
other thoughts?
Patrick F. Smith, Pharm.D.
Assistant Professor of Pharmacy
The State University of New York at Buffalo
373 Cooke Hall, Buffalo, NY 14260
(716)845-3281
---
=46rom: "Ram Chandra Gupta"
To:
Subject: Re: PharmPK A Brain-to-Plasma Ratio Question
Date: Thu, 24 Feb 2000 14:40:28 -0500
Organization: Pharmacokinetics & Metabolism Divi, CDRI, Lucknow, India
X-Priority: 3
I will prefer ratio of AUC
R.C. Gupta
[If you have all this data - i.e. enough to calculate AUC for=20
example, why not model the data and get an equilibrium ratio. Either=20
a reduced PBPK model or a compartmental model - db]
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For cut-and-dry empirical way of assessing brain distribution,
cmaxbrain-to-cmaxplasma ratio may provide some information. This is
a single-point measurement and if there is (usually does) a
disconnect between cmax in brain and cmax in plasma wrt time, then
the value is meaningless. I would suggest the use of
AUCbrain-AUCplasma ratio if you are able to fully characterize the
conc-time profile or with limited sampling, at least multiple point
estimates.
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This looks real good on paper however, would you please expand on how
to test this in humans. Specifically, in Children. How do you get
multiple data points in humans except through intra-ventricular
access. Parents are a little hesitant for us to do this. What
animal model correlates to humans so that we can extrapolate the
findings to, say a 7 month old child?
I am not trying to be a pain. I would really like to hear from the
research world how they are sampling for dosing(absorption),
distribution, metabolism and excretion in children.
As a follow up to this, we are a receiving center for all head trauma
in a 12 county area (1.1million people). During the course of a year
we see a number of patients come with IVP drains, sensors. We also
routinely draw from these area and check the CSF for bacteria, yeast,
etc. Would it be also possible to use the same specimen for drug
levels. What is the limitation if we are scavenging from samples
already drawn?
If this is too elementary, please respond to me privately.
thanks.............. Robert
Robert Aucoin, RPh 1-888-765-7428 (Toll free)
Senior Clinical Pharmacist/Operations fax: 225-765-8410
The Children's Center at Office: 225-765-7652
Our Lady of the Lake RMC pager: 225-237-6564 (digital)
Baton Rouge, LA 70808 e-mail: RAucoin.-at-.ololrmc.com
web site: www.mraucoin.com (new, under constru)
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Most studies of CSF penetration in adults and children are
opportunistic. The individuals are scheduled to undergo lumbar puncture
and the specimen is obtained along with the routine CSF specimens. Even
if the individual has a ventriculostomy, CSF should only be taken for
drug assay only when there is a clinical indication to do so or when CSF
is being removed for other reasons. This is because manipulation of the
device increases the risk of infection. There are patients with
hydrocephalus that undergo regular procedures to remove CSF. In this
case multiple specimens can be obtained, but only about every 24 hours.
However, the physiology of CSF flow is altered in these individuals.
Usually, one has to rely on one specimen per individual. Doses of the
drug of interest can be administered at varying times prior to the
expected CSF collection. CSF concentrations are examined in relation to
dosing regimen/time of last dose for a population of N individuals which
allows construction of a population "curve" for CSF penetration. The
trouble with acute meningitis is that it is impossible to time the
samples relative to dosing. CSF should be obtained prior to the first
dose of antimicrobial agent unless the tap is delayed. It is not
uncommon if chronic meningitis or in bacterial meningitis with
questionable response to obtain one or more repeat CSF taps.
David Nix
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>Most studies of CSF penetration in adults and children are
>opportunistic. The individuals are scheduled to undergo lumbar puncture
>and the specimen is obtained along with the routine CSF specimens.
Depending upon the presentation, we do an LP prior to starting
antibiotics. If the case is a true meningitis, the BBB is altered
and the amount of drug crossing is likewise altered. It has been my
experience that subsequent LPs are done to check for CSF sterility.
At that time I could get a sample, but it would do little good 3 days
down the line.
>Even if the individual has a ventriculostomy, CSF should only be taken for
>drug assay only when there is a clinical indication to do so or when CSF
>is being removed for other reasons. This is because manipulation of the
>device increases the risk of infection. There are patients with
>hydrocephalus that undergo regular procedures to remove CSF. In this
>case multiple specimens can be obtained, but only about every 24 hours.
Good point. About the only time we will sample regularly is if the
ICP is continuing to rise and removal is done to prevent herniation.
In these cases the mechanics of the brain are also altered to some
extent. What that extent is, I don't know. It would seem logical
that increased ICP will affect the BBB much like meningitis.
Pressure alone may loosen the tight junctions.
>However, the physiology of CSF flow is altered in these individuals.
>
>Usually, one has to rely on one specimen per individual. Doses of the
>drug of interest can be administered at varying times prior to the
>expected CSF collection. CSF concentrations are examined in
>relation to dosing regimen/time of last dose for a population of N
>individuals which
>
>allows construction of a population "curve" for CSF penetration. The
>trouble with acute meningitis is that it is impossible to time the
>samples relative to dosing. CSF should be obtained prior to the first
>dose of antimicrobial agent unless the tap is delayed. It is not
>uncommon if chronic meningitis or in bacterial meningitis with
>questionable response to obtain one or more repeat CSF taps.
[Back to square one. We are limited to the number of samples we can
obtain. Limited to the times we can take them. And I am not willing
to increase the danger to a child for "maybe" research.
I appreciate your comments....
>David Nix---
[Aucoin, Robert]
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