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To Sunita's question on "Evaluation of Efficacy of Prodrugs in mice " Drs.
Chugh and Stephan suggested bioavailability estimation of prodrugs in rat
model. I too agree to this with my limitation in application of this
approach to go no go decision for development of significantly superior
prodrug: Take an example where innovator's prodrug has 40% oral
bioavailability of the active moiety and the new prodrug is aimed on
improving upto 60% in clinics. What should be the best animal model (rat,
dog or monkey), study design and number of animals?
Assuming this new prodrug is safe, then to test whether this approximately
20% difference in bioavailability in animals is translated into human or
not, and to achieve the ultimate goal of filing NDA to USFDA, what should be
the study design and number of subject number for Clinical BA studies.
Surely, this difference in BA will be an USP over the innovator's prodrug?
I look forward to enrich from the experience of peers.
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The following message was posted to: PharmPK
As to your first part of the query - Unfortunately, we do not have the
shortcuts in our type of work. The oral bioavailability of the prodrugs has
to be assessed in all the species till dog. The improvement seen if any in
rodents is not reflected in dog - than probably we might have to use the
monkey. This is the approach that we are following in our studies.
But as a starting point we always use Rat PK profiling. We take at least 10
fasted rats of around 290-320g and do the serial sampling from each rat
upto 6-8 hrs and if the analytical method is not too sensitive, we pool the
samples horizontally to increase the volume size for analysis. And rank our
compounds based on rat PK data. Than we do the dog PK studies to confirm
our rodent PK results. Based upon the dog data, the selected molecules are
taken up for in vivo efficacy experiments in mouse. Significant improvement
in ED50's indirectly tell us about the improvement in mouse
I am not too sure about the clinical studies. I would be looking forward to
seeing some answers from other people for that.
Wockhardt Research Centre.
I am not too sure
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