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We are woking on finding new anti-HIV from medicinal herb. Finally, we
found some. However, we will start clinical study in a few month. We had
the LD50 in rat. Could you please recommend me how can we calculate the
first dose in man? Can I use the same method for extrapolation of dose
when I had the LD50 in mice? Thank very much for helping me.
Department of Pharmcy
Faculty of Pharmacy
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[A few replies - db]
From: David Claghorn
Subject: RE: PharmPK First Dose in Man
Date: Fri, 4 Sep 1998 14:08:26 -0500
It helps a whole lot to know the mechanism of toxicity in your study animals
and then try to "guesstimate" which is closest to man. After you have
determined LD 50, what is your MTD? In my experience, starting dose is
generally 1/10 the MTD from your animal data.
C. David Claghorn, Pharm.D.
Director, Preclinical Reports & Submissions
Subject: Re: PharmPK First Dose in Man
Date: Mon, 7 Sep 98 10:01:05 +0100
From: Andrew Sutton
To: "Pharm PK"
"Multiple recipients of PharmPK - Sent by"
Dear Korbtham Sathirakul:
I run a unit with a Pk colleague where we design early stage studies from
1st dose to man through to Phase 2a.
If I had to offer you just one really important comment, it would be to
focus on the active concentration of your new product as opposed to the
dose. It avoids extrapolating doses from rat to man which is not an exact
science... Focussing on concentration at the site of activity allows you
to calculate a human dose from assuming that the desired concentration
will be located in the vascular compartment of the volunteers (say 6
litres), so you simply multiply the concentration by that volume. You
will almost certainly not achieve the full concentration because the
volume of distribution will probably be greater, the more so if your
compound is lipophilic. This gives a useful safety factor, though you
should also start with a dose which is an order of magnitude less that
100% depending on the animal toxicity/inherent risks in mode of action
etc. If you can assay plasma levels on the earlier doses then it is
possible to estimate the true volume of distribution before you get to
the full dose.
This means that contrary to the obvious expectation SLOW IV doses are
more predictable and therefore probably safer than the oral route,
provided always that a low dose is used at the start. (I think this way
from being an anaesthetist since we used to give thiopentone to
patients..and I wouldn't mind betting that thiopentone is a lot more
toxic than your compound.) However, some companies baulk at doing the
safety tests both orally and IV..though in my opinion that is very sjort
sighted, the additional cost of short term IV toxicity being very small,
and something you want to know anyway.
Fundamental to all this will be a reliable assay ..an absolute essential
for drug development nowadays.
Guildford Clinical Pharacology.
Guildford Clinical Pharmacology
Telephone +44 (0) 1483 406886
Date: Fri, 04 Sep 1998 14:03:50 -0500
From: "Masood Bhatti"
Subject: First Dose in Man -Reply
Can you please provide a little detail about the Pharmacokinetics
profile of the drug in rat? Have you done any ADME study in any other
specie other than the rat?
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