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The following message was posted to: PharmPK
Dear members,
An injectable subcutaneous implant containing a drug is efficacious
for 4 weeks in dogs. There is good correlation between serum
concentration of the drug and its pharmacological effect although the
site of action is different. The serum level of the drug falls just
below quantitation limit (100 pg/ml, RIA) after three weeks.
To find out the serum concentration after three weeks, one of the
suggestion was to place two identical implants at two different sites
and measure the serum concentration to get the average concentration
for one implant (hopefully, the concentration will be above
quantitation level).
If the clearance of the drug is not affected at much higher doses,
what are the criticisms for this suggestion?
I would appreciate your input.
Thanks,
Delwar
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The following message was posted to: PharmPK
My initial criticism would be of the ethics of performing further
experimentation on the dogs when application of pharmacokinetic
modelling to the concentration time data you already have may give you a
good prediction of the concentration at 3 weeks.
Perhaps you could give some justification for why you need to be able to
measure the concentration at 3 weeks rather than predict it from
existing data?
--
Nick Holford, Divn 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)373-7599x6730 fax:373-7556
http://www.phm.auckland.ac.nz/Staff/NHolford/nholford.htm
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Dear Delwar:
It may come as a bit of a surprise, but there actually is no
lower limit of quantification of an assay when you are doing PK
studies. The idea comes from toxicology, where the sample itself is
the only source of information as to whether the drug is present or
not. In toxicology, there is no other source of information about the
sample than the sample itself.
However, when doing PK or PKPD work, there is much other
information. For example, you know when the drug was given, and when
the sample was drawn. From this, at least for the majority of drugs
that have linear PK behavior, we know that the last molecule
essentially never goes away.
So we are not asking if the drug is present or not. We know
it is present, and we are only asking to what degree - how much - is
present. You can determine the SD of an assay right down to and
including the blank. Do not worry that as the concentration
approaches zero,that the CV becomes infinite. The SD and the
variance, and thus the Fisher information of the data point, all are
finite, all the way down. The idea of a lower detection limit is
quite valid for toxicology, but not for PK work, where it is an
illusion.
Go to our web site (see below). Go to teaching topics, and go
to number 12, determining the assay error. There is a discussion of
this, and related powerpoint slides. This was also discussed
specifically in Jelliffe et al, Ther. Drug Monit. 15: 380-393, 1993.
Let me know what you think.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine, USC
USC Laboratory of Applied Pharmacokinetics
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.at.hsc.usc.edu
Our web site= http://www.usc.edu/hsc/lab_apk
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The following message was posted to: PharmPK
If the dose of two implants at a time doesn't give a
serum conc. higher than the MTC, then its not bad idea
to try it. but isn't it possible to set different time
points in the study by which u can extrapolate the
conc after three week?
best luck
sanjay
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)