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The following message was posted to: PharmPK
Dear PharmPK-list,
I am attempting to find guidance regarding animal dosimetry studies
to support a clinical 14C ADME study. Does anyone have a sense of
what levels of radioactivity typically will trigger the need for
animal dosimetry, 1 uCi, 5 uCi, 100 uCi?
I am aware it will be compound specific and based upon tissue
accumulation/residence time calculations but there must be some
general guidelines out there, ICH?? FDA?? WHO??.
Thanks in advance
Steve Dueker
President
Vitalea Science
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The following message was posted to: PharmPK
Dear Steve,
A little while ago I wrote a chapter on preclinical mass balance
studies for a book series to be published somehwer this summer. I had
written a similar manuscript on human mass balance studies (Clin
Pharmacokinet. 2006;45(1):33-58), where specific regulations do
apply. I was unable to find similar regulations for animals, and I
have my doubts they exist. I think in this case the best thing to do
is abide by the ALARA principle (as low as reasonably achievable).
Estimate how much radioactivity you will need for analytical
purposes, possibly increase it a bit to be sure, and do a pilot study
to confirm the chosen dose is enough. Typical radioactive doses I
found in the literature are: 1-2 uCi/mouse, 5-20uCi/rat, 5-100 uCi/
dog, 40-120 uCi/monkey, and about 100 uCi/human. If you are around
these values, you should be fine.
Recently, our lab did use a rather high dose of 30 uCi/mouse, simply
because the compound was eliminated rapidly and the 14C label was
lost as CO2. So I guess it depends on the situation.
In addition, the radiation damage to tissues is mainly relevant for
long term effects. Animals will be sacrificed relatively soon after
dosing, so that's less of an issue as it would be with humans.
Kind regards, Jan
--
Jan Hendrik Beumer
Pharm.D., Ph.D.
Assistant Professor Pharmaceutical Sciences
School of Pharmacy
The Hillman Cancer Center
Research Pavilion, Suite G.27d
5117 Centre Avenue
Pittsburgh, PA 15213-1863
Tel.lab.: +1-412-623-3238
Tel.off.: +1-412-623-3216
Fax.: +1-412-623-1212
Email: beumerjh.at.upmc.edu
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The following message was posted to: PharmPK
Dear Jan,
Thanks for the useful information. I was in fact interested in what
level of human radiation exposure would necessitate the need for
doing supporting preclinical animal dosimetry studies. We are a
microdosing company and do human mass balance/ADME studies type
studies (albeit with subpharmacologic chemical exposures) using 100
nanoCuries or less of dose activity. On rare occassions, a sponsor
may decide to use higher radiative doses, say 1-2 uCi, and I am
wondering at what point an animal dosimetry study would have to be
undertaken to shown the absence of excessive tissue accumulation of
the isotope, particularly in sensitive organs or tissues, in order to
proceed with the human study (assuming healthy volunteers)
I think this an important question as the exploratory INDs often
require the use of radioactive isotopes, be it gamma emitters for PET
or 14C beta emmitters for Accelerator Mass Spectrometry. I can not
find a clear answer from my searches although I beleive it must be
significantly higher that 1 uCi.
Thx,
Steve
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Dear Steve,
I haven't been following this conversation, but you are correct in
that nonclinical studies are often used to provide radiation absorbed
dose estimates for PET or SPECT research work, particularly in
subjects who will not receive a direct medical benefit themselves
(although there is a move toward measured whole body dosimetry
acquired in humans).
The nature and level of the data required will depend on the
regulatory body approving the study, and the position of the
regulatory body where any sponsor is based, or wishes to file data.
Essentially the aim of the exercise is to produce a plausible
estimate of the effective dose (Sv/MBq) for the tracer, which along
with the injected activity required for a decent signal, will tell
you how many scans you can conduct without exceeding the local limits
(which also vary). As you mention there are other constraints such as
critical organ doses.
As far as I'm aware, just about everyone (except the US) works to the
recommendations laid down in ICRP 60, so that might be useful. I
would also look at ICRP 62 as it adds a little to the often cited WHO
recommendations from 1977.
Lastly I would suggest looking at the dose-related literature section
of the following web-site www.doseinfo-radar.com which involves the
'dosimetry guru' Mike Stabin
I hope this helps,
Rob
Robert A. Comley
Imaging Scientist, Clinical Molecular Imaging, GlaxoSmithKline
Visiting Research Scientist, PET Research Department, Centre for
Addiction and Mental Health
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The following message was posted to: PharmPK
Steve,
On Nov 16 2004, the FDA held a workshop on "Radioactive Drugs for
Certain Research Uses." The transcript of the meeting and associated
presentations can be found on the FDA website (just go to www.fda.gov
and search for Radioactive drugs. The first search result is the one
that you should follow. Additionally, there are presentations by the
FDA Radioactive Drug Research Committee Program Presentations that may
be useful. They can be found at
http://www.fda.gov/cder/regulatory/RDRC/RDRC_presentations.htm.
These materials may help answer your question.
Regards,
Mark
Mark N Milton
Senior Director, Development DMPK
Millennium Pharmaceuticals Inc
75 Sidney St
Cambridge, MA02139
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