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Hi,
we are evaluating some ester prodrugs in mouse systemic infection
models. The idea is to look for improvement in efficacy by 20-30%.
However ED50 values are not reproducible. Unless you get reproducible
values it is difficult to comment about the activity of compounds. My
question is : Should we use systemic mouse models for such expts.or
we should rather look for improvement in PK parameters.
thanks
Sunita Malhotra
Research associate
Government Medical College
Chandigarh
India
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The following message was posted to: PharmPK
Greetings Sunita...
One must remember that the profile of a successful drug candidate is a
balance of many parameters including physical/chemical properties, toxicity,
pharmacokinetics and efficacy. My suggestion would be to consider all of
these when 'ranking' molecules. It may be that the variation within the
model is too large to 'tease out' minor improvements in efficacy when you
already have molecules that have reached a specific activity. It is at this
time when evaluation of other parameters (i.e. P450 inhibition, protein
binding, toxicity, pharmacokinetics...etc.) becomes important so that the
molecule(s) with the best chance for clinical success are chosen. Some
institutions are adopting a multiple phase approach to drug
discovery/development. Depending on which 'phase' you are in can determine
what parameters become important for ranking molecules. In the early
stages, when many compounds are being evaluated, it may be enough to
evaluate potency. However as all molecules evaluated reach comparable
potency, other parameters (i.e. pharmacokinetics, toxicity...etc.) become
useful to 'rank' potential success. I would suggest thinking about what
phase your molecules are in and go from there. My guess is that they are
all fairly active and consequently improvements in other parameters (i.e.
pharmacokinetics and toxicity) may be more useful in ranking. Hope this
helps....
Tom Stephan, Ph.D.
ICOS Corporation
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[Two replies - db]
From: YChugh.-a-.wockhardtin.com
Date: Thu, 17 May 2001 14:57:02 +0530
To: david.aaa.boomer.org
Subject: Re: PharmPK Evaluation of Efficacy of Prodrugs in mice
The following message was posted to: PharmPK
Dear Sunita,
Mouse systemic infection model is typical in the sense that it's difficult
to observe an improvement of 20 - 30%. and it depends on what organism you
are using. You should not be using very resistant strains. Sensitive to
intermediate resistant strains would give you a better picture.
ED50's in mouse would improve if the bioavailability of a compound improves
by more than 45-50%. Even with an 20-30% improved bioavailability of one
compound over the other, ED50's don't change in mouse model of infection.
While dealing with such situations we first determine the absolute
bioavailability of compounds and than look for their efficacy. Infact, we
do the rat bioavailability studies also before checking for the efficacy.
Hope this helps.
Yati Chugh Ph.D
Aurangabad.
---
From: bangarurk.aaa.drreddys.com
Date: Thu, 17 May 2001 18:43:40 +0530
To: david.aaa.boomer.org
Subject: Re: PharmPK Evaluation of Efficacy of Prodrugs in mice
The following message was posted to: PharmPK
From your question it is difficult to comment on the type of studies we
need to go with because what dose you have used and nothing about the
bioavailability is known.
What about the invitro micro- biological methods, what type of IC50 values
and IC 90% you have obtained , based on those results and combined with the
pharmacokinetic results you can fix the dose that is necessary for your end
antimicrobial activity in the same species.
I hope this will helpful in arriving at a reasonable strategy.
Good luck,
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