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I am putting up a rather general question to the group for some opinion
on a issue which relates to the repeat dose tox of a compound in rodent
and non rodent species.
The compound has a very poor rodent(Rat)PK properties in terms of
systemic exposure, however, in dog it shows excellent serum levels
which can justify the tox study. Poor rat profile might be due to many
reasons and some of them we have been able to pin down.
But Can we further develop such a compound AND HOW - because FDA would
ask for rodent tox data and in any way we would not be able to produce
the required systemic exposure. We did try hamster also but without
success.
I would appreciate some comments from the experts on the group.
Sandeep.
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It sounds like your compound is sticking to a particular protein(s) in
the plasma. Binding to this protein(s) may vary between species. You
may want to do a protein binding assay with your compound in mouse,
rat, hamster, guinne pig, rabbit, dog, pig, monkey and human serum AND
plasma. The results may foretell the PK profile in each species.
Next I would consult with the FDA regarding the situation to see if
another rodent species could be substituted based on the data you have
observed.
Charles Engbers
ALZA CORPORATION
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The following message was posted to: PharmPK
Dear Sandeep,
For simplicity I will assume that your drug is active as the parent
drug. To
comply with the rules for registration with any authority, you will
have to
submit toxicity data in a rodent and a non-rodent species. Your dogs
have
nice systemic exposures, but your rats do not.
You should consider:
1 The human exposure and metabolite profile: you need to check to what
extent your tox species have been relevant for safety testing. The
situation
is different when your human has nice plasma exposures than when the
human
has little to no exposure.
2 Data in two relevant toxicity species need to be submitted, unless
you
can justify its absense.THat is hard to do.
3 To do so you will have to have checked at least a number of rat and
mouse strains. When metabolism is the complicating factor, in vitro
metabolism studies with liver microsomes or hepatocytes from different
animal species can be a quick way to limit the number of in vivo
studies.
Please keep in mind that not all rodents are easy to get accepated as a
toxicology species.
4 If you can find an alternative rodent species or strain,-unless you
will
be able to use a mouse- it wil be prudent to obtain regulatory advice
(from
FDA )on your decision to change the rodent species.
In general, you can develop such a compound- at least we did-, but it
will
need some carefull thinking and testing to come up with a solution.
Please
realize that such a decision will also impact on the reprotoxicty
studies in
rats. If the rat has no expsoure to the active moiety, the outcomes in
rats
will be useless.
Hope this helps a bit,
Anja
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)