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We are currently in the early stages on development of an ester
prodrug. Early exploratory work has indicated that the prodrug is
rapidly hydrolysed to the active drug in rodent plasma. We do see some
prodrug concentrations slightly above our limit of detection in the
early time points however, such is the rate of the conversion, the
ratio of prodrug to active is typically 1:10000. Bioanalysis of the
prodrug in rodent species is very difficult due to the stability
issues. In non-rodent species significant levels are pro-drug are
observed. A question has arisen relating to whether there is any value
in monitoring the prodrug in future rodent studies. Are there any
regulatory requirements or precedents that cover this specific issue?
I would be grateful for any feedback. Thanks
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Regarding any need for monitoring a labile ester prodrug in animal and
human studies, my groups in the past have worked on several of such
drugs, including valganciclovir, mycophenolate mofetil, both of which
are registered, and several others (Syntex, Roche). Drug behavior in
rodent and human was exactly as you describe.
I'm not aware of specific regulations that required analysis for
labile prodrugs, but our understanding at he time of the work we did
was that we needed and wanted to understand what happened to
administered drug. The recent guidance on safety testing of
metabolites may be of further guidance.
We validated methods and tested samples from at least one study in
each animal species and in human to confirm that levels of
administered prodrugs were negligible compared to active drug. This
meant keeping drawn blood cold, freezing plasma quickly at -70,
processing samples rapidly, and allowing wider acceptance criteria for
the prodrug. In each of several cases, regulatory authorities agreed
with our proposal to discontinue monitoring the prodrug after the
initial results from one or two studies confirmed that the prodrug
concentrations were low and transient compared to active drug.
Tom
Thomas L. Tarnowski, Ph.D.
Bioanalytical Development
Elan Pharmaceuticals, Inc.
800 Gateway Boulevard
South San Francisco, CA 94080
thomas.tarnowski.-a-.elan.com
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The stability of the prodrug will impact the apparent stability of the
metabolite. As the parent converts, the active metabolite may fail
stability indicated by exceeding tolerance on the positive side. An
effort must be made to stabilize both prodrug and metabolite in
collected samples through use of preservatives, collection conditions,
etc.
--
Ed O'Connor, Ph.D.
Laboratory Director
Matrix BioAnalytical Laboratories
25 Science Park at Yale
New Haven, CT 06511
Web: www.matrixbioanalytical.com
Email: eoconnor.-a-.matrixbioanalytical.com
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