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Dear All:
We have a compound (XYZ) which is administered IV, in late stages of
development. The current form of the compound is as a sodium salt
(XYZ-sodium) but the arginate salt of the same (XYZ-arginate) promises
to have superior physical characteristics which would help with process
development.
If we decide to make this shift, what studies are required to show that
the sodium salt and arginate salt are similar in all aspects? Is release
testing sufficient or do we need extended characterization? Would any in
vitro/animal PK work be needed to show that they behave in a similar
manner? Since this is an IV drug, dissolution testing may not be very
useful. I also don't think there is a need to repeat any human clinical
studies, right?
I would be interested in hearing your views.
Thanks
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Hello Martin,
You might find the following article of interest.
" Generic substitution: The use of medicinal products containing
different salts and implications for safety and efficacy
R.K. Verbeeck, I. Kanfer and R.B. Walker"
http://eprints.ru.ac.za/797/1/walker_gen_subs.pdf
In this commentary, scientific facts/data will be presented to show that
establishing bioequivalence between oral drug products containing
different salts of the same active substance, will usually not suffice
to claim therapeutic equivalence and consequently
substitutability/interchangeability.
There are a lot of references to regulatory guidances and they discuss
tox testing.
Susan
Susan Shoaf, PhD
Director, PK/PD
Otsuka Pharmaceut. Develop. & Commercialization
Rockville, MD 20850
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Hi Martin-
I agree with Susan Shoaf that in my experience even a change of
counter-ion for a drug that is injected IV after it is dissolved will
need a substantial amount of work. You may even need to repeat tox
studies, since theoretically there could be effects that depend on the
salt counter-ion.
You should probably consider getting advice from a regulatory CMC expert
to see what you might be expected to do and what your options are.
-Tom
Thomas L. Tarnowski, Ph.D.
Director, CMC and Bioanalytics
Department Head, Biopharmaceutical Development
Elan Pharmaceuticals, Inc.
180 Oyster Point Boulevard
South San Francisco, CA 94080
thomas.tarnowski.aaa.elan.com
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Hi Martin-
I agree with Susan Shoaf that in my experience even a change of
counter-ion for a drug that is injected IV after it is dissolved will
need a substantial amount of work. You may even need to repeat tox
studies, since theoretically there could be effects that depend on the
salt counter-ion.
You should probably consider getting advice from a regulatory CMC expert
to see what you might be expected to do and what your options are.
-Tom
Thomas L. Tarnowski, Ph.D.
Director, CMC and Bioanalytics
Department Head, Biopharmaceutical Development
Elan Pharmaceuticals, Inc.
180 Oyster Point Boulevard
South San Francisco, CA 94080
thomas.tarnowski.-at-.elan.com
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The following message was posted to: PharmPK
Dissociation rates will vary depending on the salt and some salts,
e.g., lithium may have effects on other tissue and matrix
constituents.
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