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Dear all:
I am new to this field. I find this discussion group is very helpful for me
to understand PK and metabolism related topics.
I have one basic question to ask to the group; how much the in vitro drug
metabolism data is weighed in terms of drug development?
For example: if a compound shows good activity in animal efficacy studies,
but it shows less desired profile in in vitro metabolism studies (it is both
3A4 substrate and inhibitor). Can one make a decision (favor or not favor)
based on this result? And why?
Is this a common question being asked during drug development/discovery? Are
there any correlations between in vitro data (prediction) and in vivo
output/results? Any opinions or references will be appreciated.
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The following message was posted to: PharmPK It does not appear that
anyone responded to your post.
A simple reply would be to say that if all 3A4 substrates were
eliminated, a great many drugs that are now on the market would not
have made it.
Just because a compound is a substrate does not mean that it is
useless. It is a matter of degree. Saquinavir is a 3A4 substrate, and
has oral bioavailability of less than 1%, yet it was first in class,
so it was useful. Midazolam is a 3A4 substrate, and has nearly equal
gut and liver metabolism (about 45% for each), but it is useful.
Assessing the impact of the metabolism is the key to making decisions
about whether a candidate should be continued or dropped. This is now
possible through state-of-the-art simulation and modeling methods.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (SIMU)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
E-mail: walt.aaa.simulations-plus.com
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Hello Be,XuHai
In reply to your basic question, how much the in-vitro drug
metabolism data is weighed in term of drug development;
In-vitro studies can give information on:
-Metabolite identification
-Metabolite stability
-Metabolite profile
-Interspecies comparisions
-CYP induction/inhibition
-Species selection of toxicology studies
-Drug-drug interaction studies
-CYP isoform identification
-Phase II enzyme study
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There are number of very useful drugs which are substrates for CYP 3A4
including verapamil, nifedipine, cyclosporin, midazolam, etc. If one had a
rule not to develop any drugs that are substrates of CYP 3A4 then we would
have missed may useful therapeutic agents. Having said that, it is also true
that many of the recently withdrawn drugs due to dangerous drug interactions
have been substrates/inhibitors of CYP 3A4 (Seldane, mibefradil, cisapride,
etc). In judging potential candidates for clinical development of a drug
which is a substrate/inhibitor of 3A4, I would consider the following:
1. Is the drug's metabolism predominantly mediated vis CYP3A4 or there are
multiple isozymes responsible for metabolism and CYP3A4 is just one of them.
In this case I would not be greatly concerned.
2. What is the IC50" If the drug is a potent inhibitor at plasma
concentrations achieved in vivo then I would have severe reservations in
developing such a drug especially if the drug or its active metabolite (also
a 3A4 substrate/inhibitor) has a very long half life.
The above two criteria have been very useful and based on these criteria one
can see that verapamil, cyclosporin, midazolam, nifedipine have all been
successful drugs. Also based on the above criteria mibefradil (potent
inhibitor of 3A4 and has a relatively long elimination t1/2) should have
never been developed.
I hope the above information is useful to you.
Regards,
Aziz Karim
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