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The following message was posted to: PharmPK
Does anyone know of good references on good PKPD correlation when drug
concentration at site of action is high and no correlation with low drug
level?
Thanks,
Joan
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The following message was posted to: PharmPK
Joan,
Lin_Joan-En wrote:
> Does anyone know of good references on good PKPD correlation when
drug
> concentration at site of action is high and no correlation with low
drug
> level?
In my opinion there cannot exist many good references to describe this
phenomenon. I say this because of my belief that biological systems
respond in a continuous and graded way to drug concentration. If you
really know the concentration at the site of action (as your question
implies) and you know you can reliably measure a drug response then I
know of only one mechanism that might come close to producing 'a PKPD
correlation at high concentration' and 'no correlation with low drug
level' - but even this is an example of a secondary drug response and
not the primary drug effect.
Drugs which influence ion conducton in excitable tissues e.g. sodium
channel blockers acting on the Purkinje fibre system in the heart, are
expected to produce a graded change in things such as conduction
velocity. However, if the response being observed is a re-entrant
circuit arrhythmia then the re-entry pathway will suddenly block at a
certain conduction velocity and the arrhythmia will stop. If you were to
measure drug concentrations around the re-entry circuit fibres you would
observe no effect on the arrhythmia at concentrations less than the
threshold conc for blocking the circuit and total loss of arrhythmia at
concs above the threshold.
Best wishes,
Nick
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.aaa.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
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The following message was posted to: PharmPK
Joan,
This sounds like a possible application for PBPK/PD modeling, wherein
the
estimated concentration in the target tissue can be used to build the PD
model instead of plasma concentration.
Best regards,
Walt Woltosz
Chairman & CEO
Simulations Plus, Inc. (NASDAQ: SLP)
42505 10th Street West
Lancaster, CA 93534-7059
U.S.A.
http://www.simulations-plus.com
E-mail: walt.-at-.simulations-plus.com
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The following message was posted to: PharmPK
Hi,
I'm wondering about the accuracy of your drug assay method at lower
concentrations as well as sensitivity and specificity of your PD
assessment across range of concentrations, which can affect PK/PD
correlation.
Rgds,
Khalid Alkharfy
College of Pharmacy
King Saud University
Riyadh, Saudi Arabia
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