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Good morning,
Is it possible to justifyed an inverse relationship between dose and
concentration? I mean, what could be the reasons for an inverse
relation in the concentrations when the dose increase?
Thanks in advance
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The following message was posted to: PharmPK
Saturation of a protection mechanism
Oliver
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Interesting. Did you see this in animal or clinical studies? Was it
after single or multiple doses?
Ganesh
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If the drug was given orally, it could be saturation of the absorption
process especially if the drug is absorbed by a specific transporter
or carrier mediated mechanism?
--
Manish Issar, Ph.D
Applied Biopharmaceutics
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But wouldn't all of these "saturation" effects appear as a plateau
rather than an inverse relationship?
C Cole
NAH
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[A few replies - db]
Perhaps you could post some data or other observations so as to permit
more than frivolous speculation. For example, if your concentrations
approach something in the range of infinity following a placebo dose,
then I'd be inclined to think you truly have an inverse relationship
between dose and concentration. Otherwise, I am inclined to think
some other prosaic factor is at play.
Jeff
--
Jeff Wald, PhD
jeffrey.a.wald 'at' gsk.com
Director, Clinical Pharmacology Modeling and Simulation
RTP, NC
--
Could you please provide more insight, are you talking about flip-flop
kinetics for A.D.M.E. or individual components. Others have also asked
about single vs multiple doses.
thanks,
--
Sanjeev Thohan, PhD
SARx Consulting
SARxconsult.-a-.Gmail.com
--
If you give more details e.g. what range of doses, what route, when
concs were measured then perhaps a sensible answer could be provided.
--
Nick Holford, Dept Pharmacology & Clinical Pharmacology
University of Auckland, 85 Park Rd, Private Bag 92019, Auckland, New
Zealand
n.holford.-at-.auckland.ac.nz
http://www.fmhs.auckland.ac.nz/sms/pharmacology/holford
--
Dear PKPD Doubt,
Subject to the study design, I would want to rule out experimental
error first rather than some mechanism. This phenomenon may be due to
degradation of the drug in solution. For example, if such a drug is
reconstituted/thawed and the higher dose is studied at later times
compared to the lower doses. This may result in the drug being
degraded to a larger extent in the higher dose group. Essentially, you
may be injecting a lower dose of the intact drug.
Another possibility may be due to degradation of the drug ex-vivo in
the sample matrix. This again could be accounted for by treating the
samples consistently with regards to time.
Anson Abraham
University at Buffalo
anson.ab.at.gmail.com
--
The following message was posted to: PharmPK
Suppose the drug formed a concretion and changed the pH. One would
mechanically reduce the amount of drug available, the other would
chemically
reduce the amount of drug (form) available.
Bioconsul09.at.cox.net
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Yes, of course
The fact is that in preclinical and very early clinical study you can
observe a dose proportion but when the dose are higher the proportion
that not occurs and it start to decrease
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Hi,
This is something I have already come across in some (old) literature
(mid '80s). It was a dose-titration study with an antidepressant drug.
By design, the least responders received the highest doses.
Kind regards,
Henri
Henri MERDJAN
Vice-President, DMPK, NOVEXEL, France
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