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Dear all
I have been posed to a problem concerning the preclinical PK-PD
correlation where one of our in house anti cancer molecule showed very
superior PK data AUC of 186 ug/mL at 100 mg/ kg B.W with oral
bioavailability of about 50% in Swiss Albino Mice at the same moment
molecule have very good in-vitro activity on various tumor cell lines
and its GI-50 is around 1.9uM. When knob on to in\0x96vivo (Xenograft)
studies at 3 doses of 100, 200 and 500mg in nude mice bearing HT Cell
line, the molecule is showing 0% inhibition activity. Further this
molecule exists very stable in RLM and Mouse liver microsomes and very
good permeability too.
At the same time we are carried out some SAR studies where we replaced
the chloro group of the side ring and replaced with COCH3 and NHCOCH3
to the side ring there is very poor PK data for the later ones.
My questions regarding this issue are
What could be the basis to get this predicament
Whether our molecule is Pgp Substrate ( Yet to carry out the study),
What are the simple techniques adopted for screening the drug
whether it is PGP substrate or inhibitor other than Rodamine assay
What are the potential to perk up the efficacy of a molecule other
than SAR of the molecule
please make available me any literature concerned to this issue
Regards
Venkatesh
Venkatesh.P
Senior Pharmacologist,
Dept of Drug Metabolism and Pharmacokinetics,
Discovery Research, Dr.Reddy's Labs.
Hyderabad, India-500050.
Phone no:91-9849692908
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Hi Venkatesh
You could screen your molecule in-vivo using the md1a/b deficient mice
(that would lack the Pgp efflux pumps) versus wild type mice (express
Pgp). i had conducted some experiments sometime ago and it worked
pretty well for us. however the mice are pretty expensive hence as an
alternative the normal rats/mice could be to pretreat them with
verapamil to inhibit the Pgp and then perform your experiment. the only
catch would be to optimize the dose of verapamil and validate so that
you get consistency in the inhibition. This would be time consuming but
be cheaper than the knock out mice.
Alternatively i think there are cell lines that could be used quite
efficiently (for some drugs) to mimick the Knock out mice invitro. you
would have to see how your drug behaves there.
Good luck
Manish Issar, Ph.D
Eon labs Inc.
Wilson, NC
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If paclitaxel has GI50 in the nanomolar range, why do you think the NCE
will be effective at GI50 of uM? Maybe you did not see antitumor
activity as it is an inactive drug?
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Hai,
Lack of in vivo translation of the in vitro activity is a major problem
and there can be several reasons for that. In PK-PD correlation always
one should not go by systemic exposure (AUC) alone. You might be aware
of the concept of surrogate marker where people will identify a
suitable parameter which explains the pharmacodynamics. For example,
take linezolid where the suitable surrogate marker which explains its
pharmacodynamic behaviour is time above MIC. In linezolid's case
although you get better AUC with increase in dose the marker which will
explain the dynamics is T> MIC. So, coming to your point, identify such
a surrogate marker and then try to view your case.
Best of Luck
rkb
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Dear Venkatesh,
the following may be helpful to look into:
1) What is the in vitro model that is relevant to your in vivo model?
Have
you tested this model with reference compounds to show that there is an
in
vitro-in vivo relationship?( What is the Pharmacodynamic endpoint for
your
assay?)
3) What is the protein binding for your molecule? Have you estimated the
free AUC and Cmax in mice? Where is the target located in mice?
Cheers
Ramesh
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