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We have conducted a radiolabeled ADME study in human volunteers for a
compound in development. Results show that plasma levels of the
unchanged drug in the ADME study were significantly lower than those
seen in other single dose studies at the same dose with a similar
formulation. One of the reasons for this may be the difference in the
way the formulation was prepared. The total radioactivity recovered
in the feces was high (not unexpected) but the lack of absorption of
the drug from the GIT may be a reason for this observation. The drug
is also highly variable when given orally as seen from some previous
studies. However, the levels of the drug in plasma in the ADME study
are almost 10-20% of those seen earlier and is quite startling.
One of the objectives of this study was to determine the profile of
the metabolites in humans. However, since the overall absorption of
the compound appears to be low, metabolite profiling in a few samples
at the chosen time-points may be an issue (low radioactivity at those
time-points). It is quite possible that we may not be in a position
to detect metabolites in plasma that would have otherwise existed,
had the bioavailability been higher. My questions is to determine how
exactly to proceed from here on. What would be FDA's view on this?
Would we have to repeat this study? Would an explaination about the
high variability of the drug be an acceptable answer?
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The following message was posted to: PharmPK
Dr. Gupte,
You may be able to salvage some of the metabolite profile data using
ultrasensitive accelerator mass spectrometry techniques to detect the
14C compound.
I would be happy to arrange a discussion with Dr. Ali Arjomand at our
facility to look into the possibility.
Michael Chansler
Vice President Business Development
Accium BioSciences
550 17th Avenue, Suite 550
Seattle, WA 98122
Tel: (206) 281-3915
Fax: (206) 281-5916
www.acciumbio.com
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What was your mass balance and how many patients were dosed? also
what was the mean and STD of the plasma levels?If uour mass balance
is 95-105% and there is hight STD, then maybe you can go to the FDA.
Also do you have any blood to plasma ratios over the plasma conc
range (invivo or invitro)? If this is non-linear or dependent on
conc then this could answer some of questions raised.
Stanley Cotleer
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The following message was posted to: PharmPK
Dear Girish Gupte
Hopefully some critical issues have already been addressed in the
study. The labeling stability of the labelled test compound is critical.
The lower plasma levels of the unchanged drug in plasma may be due to
less in vivo stability of the label or due to the difference in handling
of the label in body by two formulations. It should be ascertained that
the labelled was attached with the drug and not with inactive
ingredient(s) of the formulation. Higher recovery of radioactivity in
feces may be confirmed by dynamic scintillation images at different time
occasions.
Metabolites are sometime difficult to detect as they may not retain the
radioactivity.
--
Nadeem Irfan Bukhari
nadeemirfan_bukhari.-at-.imu.edu.my
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)