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Dear all,
I have a couple of questions.
In case of CNS acting compound that has PK profiles as follows,
1) a excellent solubility in ph 7.4 phosphate buffer,
2) good caco-2 permeability
3) mid-low metabolic stability in human (20min / 5 min in rat)
4) low bioavailability in rat (5%, CL : 5 L/kg/hr)
5) excellent efficacy in ip, po in mice and rats.
6) low toxicity in ip, po in mice and rats.
is it possible to develop to the next step?
If you know the case of launcheddrugs with low bioavailaility and low
metabolic stability, please let me know.
thanks,
Yeonjung Choi
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Hi,
several thoughts come to mind:
Why not press on with development - the activity is 'excellent'
Active metabolites - keep in mind that they can be less activity but
present in
higher concentrations in the brain ?
'Low' bioavailability introduces issues around variable exposure between
individual patients and the balance of efficacy and toxicity is brought
into focus.
High metabolism rates/extents means that you will need to address the
enzyme
mediated interaction issue
This looks a fairly typical CNS-activity profile, IMHO
Best Regards
Dave
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Saquinavir is a good example of a drug that was developed initially
with very low bioavailbility (less than 5% in humans). That resulted
in administration of massive drug mass to achieve the plasma levels
required, however the potency of the drug and the need for a new drug
supercedes the bioavailability issue at the time. Higher
bioavailability formulations were later developed. One issue with low
bioavailability might be interindividual variability. You certainly
need more in-vivo PK data (dogs and/or monkey) to take an adeqate
decision (these species should be part of your metabolic stability
assay that I presume are liver microsomes).
JP
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)