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Dear All,
We are working on a NCE which was observed to follow differernt
pharmacokinetic compartment model across various pre clinical animals
models. It was found that it is following two compartment model in
rodents and one compartment model in beagle dogs. When plasma protein
binding was carried out across the species we found that its binding in
rodents is > 90 % , where as in beagle dogs its ~ 64 %. Is this the
reason for the compound to show different compartment model inrodents
and dogs??
Ifwe have to carryout allometry for the predcition of human
pharmacokinetic parameters, which way we should proceed.First and
foremost question is how to predcit the probable comapartmetmodel the
compound will follow in humans. Asprotein binding has given some
insight regarding the compound, inorder to get an idea regarding the
compartment model the compound is likely to follow in humans, we
carried out in vitro protein binding study in human and found that its
binding is > 90 %.Now can we assume that the compound is likely to
follow two compartment model in humans. In that case, we have to scale
by taking only data from rodent studies, which on doinf is not
resulting in an acceptable exponent.
Can anybody suggest a way out of this enigma.
Regards,
Ravi Kanth
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Bhamidipati,
I do not think there is any good reason to suppose that the number of
compartments required is predictable from one species to another by
using protein binding. I would expect that in any species you could
expect to see one, two or even three compartments depending only on how
quickly the dose was administered and how frequently samples were
taken.
The form of the compartmental model should not be of much concern. Of
greater interest it the ability to predict clearance and perhaps volume
from non-human to human species. Allometric scaling based on unbound PK
parameters is one step in this direction.
Nick
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
email:n.holford.at.auckland.ac.nz tel:+64(9)373-7599x86730 fax:373-7556
http://www.health.auckland.ac.nz/pharmacology/staff/nholford/
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