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To the PharmPK Discussion Group:
A recent paper has come to my attention Drug Discovery Today
Volume 4 Number 5 pages 232-237:1999 which may be of relevance to the
Discussion Group debate regarding the uses and abuses of the AUC measurement.
The report advocates a "short cut" procedure for rapid
pharmacokinetic screening of compounds in animals by estimating AUC from the
average concentration (not a steady state measurement) of pooled plasma
samples obtained during a fixed (six hour) time interval after single oral
doses of candidate compounds. The report further suggests that a rank order
based on the estimated AUC values can be constructed to prioritize compounds
for further investigation.
Even if we accept the estimated AUC calculation as a ballpark
parameter, aren't we comparing apples and oranges when we rank compounds
according to "high" or "low" AUC, without knowing anything about the Volume
of Distribution, Elimination Rate Parameters, and Fraction of Dose Absorbed
for each candidate compound? From a drug development (and drug company)
perspective, are these "shortcuts" reasonably calculated to save time and
money?
Howard S Mehler
Howard S Mehler PhD JD & Associates Inc
6399 Wilshire Boulevard Suite 310
Los Angeles, CA 90048
Voice: (310) 271-0755
FAX: (323) 782-9342
email: hmehler.aaa.mehler.com
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"howard s mehler phd jd & assoc inc (by way of David_Bourne)" wrote:
The report advocates a "short cut" procedure for rapid
> pharmacokinetic screening of compounds in animals by estimating AUC from the
> average concentration (not a steady state measurement) of pooled plasma
> samples obtained during a fixed (six hour) time interval after single oral
> doses of candidate compounds.
What is a "fixed (six hour) time interval"? Does this mean many samples
measured over 6 hours (unspecified in relation to the dose) or does it in
fact mean a single sample at 6 h after the dose?
> The report further suggests that a rank order
> based on the estimated AUC values can be constructed to prioritize compounds
> for further investigation.
Assuming a sensible sampling design after a single dose then the AUC can be
used very simply to estimate the CL/F for the compound:
CL/F = Dose/AUC
If a drug discovery group is interested in knowing CL/F then this seems
reasonable.
>
> Even if we accept the estimated AUC calculation as a ballpark
> parameter, aren't we comparing apples and oranges when we rank compounds
> according to "high" or "low" AUC, without knowing anything about the Volume
> of Distribution, Elimination Rate Parameters, and Fraction of Dose Absorbed
> for each candidate compound?
I dont see why you think this is apples and oranges. If a company wants to
compare CL/F for a series of compounds then using AUC to do this is
perfectly reasonable. Note that it is NOT possible to distinguish
differences in CL from those in F (fraction of dose absorbed) by using oral
doses alone.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, Private Bag 92019, Auckland, New Zealand
email:n.holford.-at-.auckland.ac.nz tel:+64(9)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)