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The following message was posted to: PharmPK
Would anyone care to comment on at what point does a clinical C14 study
need to be done as part of the development process. Or for what type of
compounds should this be done.
This should be an interesting discussion.
Thanks.
Peter L. Bonate, PhD
Director, Pharmacokinetics
ILEX Oncology, Inc
4545 Horizon Hill Blvd
San Antonio, TX 78229
phone: 210-949-8662
fax: 210-949-8487
email: pbonate.-a-.ilexonc.com
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[A few replies - db]
From: "Dave Vowles"
Date: Thu, 13 Dec 2001 10:28:56 -0000
To: david.-at-.boomer.org
Subject: Re: PharmPK When to do C14 Studies
Status: R
The following message was posted to: PharmPK
I would argue that a 'clinical 14C study' is a device used to address
development questions rather than a development step in itself. Accordingly
I think that the fundamental question being asked is primarily related to
metabolism and then to rates and routes of excretion ( and a bit towards
mass-balance ! ). There may be other devices to be used to address these
questions so the traditional 14C device is not a given.
However if we are to exposure volunteers to radiation then ethically it
would seem that it would be inappropriate to do so before some proof of
concept of the pharmacological activity in man is established. Additionally
since the metabolism information is useful to compare with the species used
in safety testing and efficacy models (in vivo) then the earliest provision
of this information can increase confidence in in vivo models and allow
toxicokinetics (plasma ) to explore more relevant molecules arising from the
Test Item. This may mean changing the Toxicology strategy for the longer
term studies
Obviously each development programme is unique so generalities will always
fail at some time and biologicals is an obvious one where metabolism data
may well be of limited significance in a development strategy !!
More views please
Dave
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From: "Masson, Eric"
Date: Thu, 13 Dec 2001 08:56:49 -0500
To: david.-a-.boomer.org
Subject: RE: PharmPK When to do C14 Studies
Status: R
The following message was posted to: PharmPK
This is a very interesting question Indeed. At the PPDM worshop at AAPS
Annual Meeting, there was a discussion on this topic. Although it is
compound depend as always, there seem to be a consensus that this study
should be performed before phase II, and perhaps as the third Phase I study
after single and multiple ascending doses.
Any other thoughts?
Eric Masson, Pharm.D.
Anapharm Inc.
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From: Glenn Whelan
Date: Thu, 13 Dec 2001 09:21:12 -0500
To: david.-a-.boomer.org
Subject: RE: PharmPK When to do C14 Studies
Status: R
The following message was posted to: PharmPK
what is a clincal c14 study?
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From: "Kavanagh, Ronald E"
Date: Thu, 13 Dec 2001 10:40:32 -0500
To: david.-a-.boomer.org
Subject: RE: PharmPK When to do C14 Studies
The following message was posted to: PharmPK
I believe the earlier in the drug development process such a study is done
the better.
It appears that many times these studies are done late (e.g. in the middle
or end of phase II) simply as a check off the box type of study or to guide
phase I interaction studies that are done concurrently during phase III. By
then it's too late to effectively incorporate the results into your
development program.
There's so much information to be gleaned from these studies that guide so
many aspects of the development program that it seems foolish not to have
the information early.
For example:
Metabolic pathways
Formation Clearances
Exposure to various moieties (including potentially toxic moieties)
Extent & rate of absorption
First pass metabolism
Permeability
This information can guide development in the following areas:
Genetic and ethnic group differences
special populations
drug interactions
preclinical and clinical toxicology studies
formulation developments
BCS classification
Food Effects
pharmacodynamics & PK/PD
dosing
whether it's even worthwhile to pursue development
Consequently, to wait until it's too late to incorporate the results seems
foolish. Waiting can also give you problems when you try to file an
application if issues that are readily apparent from 14C studies conducted
late in development are not adequately addressed prior to filing. In fact,
recently I heard that senior medical review management have been asking why
applications were even filed when such information is not available at
submission. (According to the CFR and guidances submissions need to be
complete at filing).
Finally, the last day of the AAPS meeting there was closed session
(registration required) to discuss drug metabolism. One of the audience
participants from industry stated that he believed such studies should be
done early. Looking around the room I noticed that all the panelists (Jerry
Collins - FDA, Shiew Mei Huang - FDA, (I believe) Paul Pearson - Merck -
Drug Metabolism, Ken Thummel - University of Washington) as well as all FDA
personnel in the audience were nodding in agreement.
Ron Kavanagh, BS Pharm, PharmD, PhD
Clinical Pharmacologist
Office of Clinical Pharmacology and Biopharmaceutics
US Food & Drug Administration
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For ethical reasons, there is almost no reason why such a
study can't be done with
heavy nonradioactive isotopes, e.g. 15N or 2H or 13C or a combination
thereof.. Then
all you need is a mass spec detector to complete the mass balance
study without the risk
of permanent damage from radioisotopes before knowledge of tissue
drug localization is
well understood.
Dan Sitar, University of Manitoba
Daniel S. Sitar, PhD
Professor and Head
Department of Pharmacology and Therapeutics
sitar.aaa.ms.UManitoba.ca
Tel: 204-789-3532 FAX: 204-789-3932
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The following message was posted to: PharmPK
Using 14C-isotopes and Accelerator Mass Spectrometry detection may be also a=
n
alternative to reduce the exposure of volunteers to radioactivity and
thus to be
more ethical. The radioactivity applied for those ADME studies is minimal.
However the technique is complicated and the instrument is huge. Therefore o=
nly
a few centres can provide such analysis.
A reference is CBAMS (Centre for biological accelerated mass spectrometry) i=
n
York, UK.
Regrads, Ren=E9
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The following message was posted to: PharmPK
I agree Rene, with the addition of another feature. It helps to be able to
easily ship samples without extra restrictions since the radiation level is
below background. We use another centre at Purdue University (West
Lafayette, Indiana) called the AMS Prime Lab (
http://primelab.physics.purdue.edu/ )
Candice Kissinger
In Vivo Sampling Laboratory
Bioanalytical Systems Inc.
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In my personal opinion, while there is value to do 14C studies as
early as possible in clinical development, there is substantial risk
to invest developmental dollars (synthesis of 14C GMP material,
animal tissue distribution, dosimetry, etc) if the new candidate in
question has to be, for example, terminated. Consequently, it may
seem prudent to initiate 14C studies after a proof of
concept/principle is demonstrated in humans. Unless, of course,
there is a metabolism/mass balance issue that necessitates performing
the 14C study after FIM or SIM.
[FIM == first in man ?? - db]
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[Two replies - db]
From: "Dave Vowles"
Date: Fri, 21 Dec 2001 10:07:51 -0000
To: david.at.boomer.org
Subject: Re: PharmPK Re: When to do C14 Studies
The following message was posted to: PharmPK
Another interesting point !!
How many people synthesis their radioactive Test Item to be used for human
studies to GMP ( can we have near-GMP ) standards ? Is it really always
required since one could argue that if the diluent [non-labelled Test Item ]
is manufactured to GMP then the vast majority of the bulk chemical will be
prepared to GMP.
Happy Christmas
Dave
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From: "A.Sutton"
Date: Fri, 21 Dec 2001 12:10:11 -0000
To: david.aaa.boomer.org
Subject: Re: PharmPK Re: When to do C14 Studies
The following message was posted to: PharmPK
I agree with Rajesh in needing to balance the cost of C14 studies with
the likelihood of the compound progressing. Since the main point of
the studies is to quantify metabolites another consideration
influencing timing is whether metabolites have pharmacological
activity. This might be particularly relevant for antibiotics or analgesics
for example.
Andrew Sutton.
Guildford Clinical Pharmacology
asutton.aaa.gcpl.co.uk
+44 (0) 1483 tel: 406886, fax: 455375
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