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The following message was posted to: PharmPK
Dear All,
How would one rank order compounds based on
pharmacokinetic parameters (obtained from either
in-vivo animal data or prediction analysis). Which are
key parameters? I am looking for some serious inputs.
Any relevant literature would be highly appreciated.
Thanking you in anticipation,
CALI
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The following message was posted to: PharmPK
The key parameters are Vd, CL and t1/2 or elimination rate constant.
For an easy guide to PK, Donald Birkett has written a simple to read
book called 'Pharmacokinetics made easy' published by McGraw Hill.
If you are interested in ranking molecules using human PK then you
can get a quick and cheap read from human microdosing studies as
outlined in either EMEA or FDA Guidelines.
Professor Colin Garner BPharm PhD DSc FRCPath
Chief Executive Officer
---
Xceleron Ltd
York Biocentre
Innovation Way
Heslington
York YO10 5NY
United Kingdom
Switchboard: +44(0)1904 561561
Direct line: +44(0)1904 561568
FAX: +44(0)1904 561560
Email: colin.garner.at.xceleron.com
Why not visit our Web site
http://www.xceleron.com
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The following message was posted to: PharmPK
Dear Dr. Garner,
Your reply suggests that simple noncompartmental or 1-compartment PK
parameters are sufficient to rank order series of compounds. I disagree.
I think that at least a few other factors are required, including,
but not
necessarily limited to: solubility, small intestine permeability, colon
permeability, IC50 for the target, plasma protein binding, and
distribution
into the target tissue(s).
For example, two molecules both have the same half-life, the same CL,
but A
has Vd = 0.1 L/kg and B has Vd = 1 L/kg. Which is better? By the way,
A is
99% bound to plasma proteins, while B is 50% bound. Also, A has an IC50
value of 1 uM, while B is 10 uM. And A has a solubility at pH 2 of
100 ug/mL
while B's solubility at pH 2 is 10 ug/mL. Oh, and A is a base with
pKa=7,
while B is an acid with pKa = 4.5. A is a P-gp substrate while B is
not, but
B is a 3A4 substrate but A is not. As you can see, it's just not that
simple. There are numerous trade-offs among potency, physicochemical
properties, formulation, regional absorption differences (due to
regional
differences in transporter expression, tight junction gap, and
ionization),
gut metabolism, systemic clearance in all its forms, and amount of drug
reaching the target tissue.
As I travel around the industry, I hear some researchers who rank order
compounds based on IC50, others on Fa or F, others on the simple PK
parameters you mentioned. With the exception of certain "well-behaved"
drugs, the interactions are just too complex for pencil and paper or
hand
calculator analyses. It is those well-behaved drugs that coerce us into
thinking we can use a simplistic approach for all new candidates. In our
experience, the industry is working on very few drugs that are so
well-behaved.
IMHO, there is only one way to assess these trade-offs - via high
quality
simulations. The state-of-the-art today is such that we are almost
always
able to pull together the data for a project and find "what the data is
trying to tell you". One can study spreadsheets, graphs, tables of
experimental values, etc. until the next millennium without
understanding
the complex interactions that cause the data to be what they are. But
with a
good simulation tool, such interactions are automatically accounted
for in
the differential equations, and finding a single model that explains
all of
the data for different doses.
Is it perfect? Of course not. But it is incredibly enlightening, and
project
decisions that can affect the allocation of many thousands to many
millions
of dollars should be based on the best analyses available.
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (AMEX: SLP)
1220 W. Avenue J
Lancaster, CA 93534-2902
U.S.A.
http://www.simulations-plus.com
Phone: (661) 723-7723
FAX: (661) 723-5524
E-mail: walt.-a-.simulations-plus.com
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Dear All,
Thats a great insight into the candidate selection process. But, for
the initial screening of candidates do we need to consider all the
factors? If a drug is having a high clearance than others, can't we
remove from the pool of compounds as a candidate? Won't it be
useless data to get all the parameters in the initial screening? The
factors such as gut metabolism, intestinal permeation etc will be
more helpful in fine tuning of the candidate selection and that will
definetely improve the efficiency of the selection process. Please
clarify some more on this issue of candidate selection.
Thanks
Ayyappa
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The following message was posted to: PharmPK
I entirely agree with Walt Woltosz. In the early days of
pharmacokinetics
people wanted a 'magic number' that summed up all the kinetic
properties of
a drug - half-life being the favourite. This was great for company
brochures (my drug is better than yours because it has a longer half-
life -
vice versa!). Computers were not so powerful (or not even used) so the
human mind was also more keen on simplification and there was the
desire to
make models as simple as possible by leaving out 'unnecessary'
complications
(Occam's Razor). Computers don't mind doing all these calculations
though,
and I am in favour of including everything in physiological based
modelling.
This also has the effect of buffering some of the values incorrectly
assumed
for a particular drug. I am sure good models are better predictors of
kinetic behaviour in Man than animal models, for which I see less and
less
relevance in pharmacokinetics.
Joe Chamberlain
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)