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The following message was posted to: PharmPK
I have noticed that patients who are placed on IV valproate that their
serum
concentrations appear to be dramatically lower compared with the same
dose
given orally (syrup, tablets or sprinkles). Has anybody else noticed
this?
If so what kind of explanation would there be for this?
Note we look only at total concentration not free, and are generally
only
looking at trough levels.
Bill Murray
Children's Hospital San Diego.
[Slower absorption could give lower peaks and higher trough values - db]
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The following message was posted to: PharmPK
When you give the drug i.v., the Cmax and peak level
may be enough to control the case clinically.
Therefore, I suggest to measure Cmax to find the
situation. Trough level reflects the capacity of the
body to eliminate the drug.
regards,
Dr. Ehab EL Desoky MD, PhD
Pharmacology Dept
Faculty of Medicine
Assiut University. Assiut.Egypt
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The following message was posted to: PharmPK
Valproic acid is absorbed rapidly and completely after oral
administration.
Peak concentration in plasma is observed in 1 to 4 hours, although this
can
be delayed for several hours if the drug is administered in
enteric-coated
tablets or is ingested with meals.
Pharmacokinetically this means that the levels after Cmax after oral
administration will be higher than those after IV administration
specially
if there is an apparent distribution phase.
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The following message was posted to: PharmPK
Bill,
Since IV valproate is typically administered over an hour I would expect
that the IV, syrup and solution troughs on the same dose and interval
to be
similar. Our experience at UCSD has typically been consistent with this
expectation.
However, I would expect the IV troughs to be lower than the troughs
following the same dose and interval given as ec tablets or sprinkles.
Jim
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Dear Ehab:
You are basically correct. However, I think you really want to
know how the drug behaves in each patient, and in the population. This
is best done by various optimal sampling designs such as D-optimal
design, for example. A good reference is D'Argenio DZ: Optimal
Sampling times for Pharmacokinetic Experiments, J. Pharmacokin.
Biopharm. 9: 739-756, 1981. These approaches have been around and well
known for a long time. It is very useful to use them in TDM, as often
we also want to know the AUC to reflect the total exposure of the
patient to the drug, and this will not be reliable unless we have a
good model of the behavior of the drug in each patient, with good
estimates of all the parameter values.
Methotrexate (MTX) is often dosed to a target AUC, for example.
However, many of the sampling strategies for MTX do not begin to sample
until after 8, 12, or even 24 hours, just to see if the patient needs
leucovorin rescue or not. Models based on such data miss much important
information about the uptake and distribution of the drug, and I wonder
how reliable the AUC's from that data really are. Use of designs such
as D-optimal sampling would greatly improve that information, I think,
and would make treatment to a desired AUC much more relevant and
reliable. Further, since we often treat to a target AUC, how do we
know that that population AUC is the really best AUC for a particular
individual patient? It seems to me that that is what individualized
drug dosage is really about.
At any rate, the basic reason for TDM is not simply to see what
the levels are at a certain time, but really to understand the behavior
of the drug in each individual patient, and to help us evaluate the
sensitivity of each patient to the drug, so we can develop the best
regimen to hit a selected individualized target goal (or an
individualized target AUC) most precisely.
Very best regards,
Roger Jelliffe
Roger W. Jelliffe, M.D. Professor of Medicine,
Division of Geriatric Medicine,
Laboratory of Applied Pharmacokinetics,
USC Keck School of Medicine
2250 Alcazar St, Los Angeles CA 90033, USA
Phone (323)442-1300, fax (323)442-1302, email= jelliffe.aaa.usc.edu
Our web site= http://www.lapk.org
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)